TW200406399A - Substituted heterocyclic compounds and methods of use - Google Patents

Abstract

The present invention relates to compounds having the general formula, or a pharmaceutically acceptable salt thereof, wherein R1 is a saturated or unsaturated 5-, 6- or 7-membered, ring containing 0, 1, 2 or 3 atoms selected from N, O and S, wherein the ring may be fused with a benzo group, and is substituted by 0, 1 or 2 oxo groups, and wherein R1 is additionally substituted; and R2 is a substituted C1-6alkyl. Also included is a method of prophylaxis or treatment of inflammation, rheumatoid arthritis, Pagets disease, osteoporosis, multiple myeloma, uveititis, acute or chronic myelogenous leukemia, pancreatic β cell destruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis, anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia, Reiter's syndrome, type I diabetes, type II diabetes, bone resorption diseases, graft vs. host reaction, Alzheimer's disease, stroke, myocardial infarction, ischemia reperfusion injury, atherosclerosis, brain trauma, multiple sclerosis, cerebral malaria, sepsis, septic shock, toxic shock syndrome, fever, myalgias due to HIV-1, HTV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses or herpes zoster infection in a mammal comprising administering an effective amount a compound as described above.

Description

200406399 发明 Description of the Invention: This application is for the benefit of US Provisional Application No. 60 / 382,699 filed on May 21, 2002. This case is attached for reference. [Technical Field to which the Invention belongs] The present invention includes a new class of compounds for treating diseases, such as diseases caused by TNF-α, IL-1β, 11 ^ -6, and / or IL-8, and other diseases such as pain and diabetes. In particular, the compounds of the present invention are useful in the prevention and treatment of diseases or including inflammatory conditions. The invention also relates to intermediates and methods for preparing such compounds. [Prior art] Interleukin-l (IL-l) and tumor necrosis factor a (TNF-a) are composed of various cells, including nucleus and macrophage cells, and they can stimulate various inflammations (such as lipopolysaccharide-LPS) or extracellular Pro-inflammatory cytokines secreted by repressive (such as osmotic shock and peroxide) responses. When the amount of TNF-oc and / or IL-1 exceeds the basal amount, it can stigmatize or accelerate a variety of diseases, including rheumatoid arthritis; Pagets disease; osteoporosis; multiple myeloma; uveitis; acute and chronic intramedullary Leukemias produced; T-cell destruction of viscera; Osteoarthritis; Rheumatoid spondylitis; Gouty arthritis; Inflammatory colitis; Adult respiratory depression syndrome (ARDS); Psoriasis; Crohn's disease; Allergic rhinitis; Ulcerative colon Inflammation; allergies; contact dermatitis; asthma; muscle degeneration; cachexia; Reiter's syndrome; type I and type II diabetes; -bone resorption disease; graft-host response; ischemia reperfusion injury; Atherosclerosis; Brain injury; Multiple sclerosis; Cerebral malaria; Toxemia; Toxic shock; Toxic shock 85481 200406399 Syndrome; Fever and muscle pain caused by infection. HIV-1, HIV-2, HI V-3, cytomegalovirus (CMV), influenza, adenovirus, herpes virus (including HSV-1, HSV-2) and band cancer therapy are also exacerbated by TNF-α. TNF-a has been reported to play a role in head injury, stroke, and local hypoxia. For example, in animal models (rats) of head injury, the amount of TNF-a in contused hemispheres is increased (Shohami et al., J. Cereb. Blood Flow Metab. 14, 615 (1994)). In the ischemic mouse model, where the middle cerebral artery is blocked, the amount of TNF-α mRNA of TNF-α is increased (Feurstein et al., Neurosci. Lett. 164, 125 (1993)). It has been reported that the administration of TNF-α in the cerebral cortex of rats leads to significant accumulation of neutrophils in the microvessels and sticks to the small arterial blood vessels. TNF-α promotes infiltration of other cytokines (IL-1β, IL-6) and chemokines (chemokinesX), and chemokines promote the infiltration of neutrophils into the blocked area (Feurstein, Stroke 25, 1481 (1994)). TNF-oc also plays a role in type 2 diabetes (Endocrinol. 130, 43-52, 1994; and Endocrinol · 136, 1474-1481, 1995). TNF-a promotes the life cycle of certain viruses and its causes Induced disease also plays a role. For example, TNF-a secreted by monocytes has high levels of HIV expression in chronically infected T cell clones (Clouse et al., J. Immunol. 142, 431 (1989 )) ° Lahdevirta et al., (Am. J. Med. 85, 289 (1988)) discussed the role of TNF-α in cachexia and muscle degradation caused by HIV. TNF-α is a cytokine cascade in inflammation As a result, an increase in the amount of TNF-a can lead to an increase in other inflammatory and pro-inflammatory cytokines such as IL-1, IL-6, and IL-8. 85481 -9- 200406399 Increased IL beyond the basal amount Amount of -1 involves causing or aggravating a variety of disease conditions' including: rheumatoid arthritis; osteoarthritis; rheumatoid spondylitis Gouty arthritis; inflammatory bowel disease; adult respiratory depression syndromes (ARDs), psoriasis; Crohn's disease; ulcerative colitis; allergies; muscle degeneration: cachexia; Reiter's syndrome; types I and II Diabetes; Bone resorption disease; Ischemia-reperfusion injury; Atherosclerosis; Brain injury; Multiple sclerosis •, Toxemia; Toxic shock; Toxic shock syndrome. Sensitive to TNF-α-inhibited viruses, such as HIV- 1. HIV-2, HIV-3 are also affected by IL-1. TNF-a and IL-1 play a role in pancreatic β-cell destruction and diabetes. Pancreatic β-cells produce insulin that helps stabilize blood sugar. Pancreas Damage to visceral β cells is often accompanied by type I diabetes. Abnormal pancreatic β cell function can be found in type Ⅱ diabetes. Type π diabetes is characterized by functional resistance to Tengdaosu. In addition, type η diabetes is often accompanied by plasma Elevated glucagon and increased glucose production in the liver. Glucagon is a regulatory hormone that inhibits gluconeogenesis in the liver with tenanthin. Glucagon is now found in liver, kidney, and adipose tissue Receptor. Glucagon antagonists can be used to reduce plasma glucose content (WO 97/16442, the entire text is attached for reference). It is generally believed that by antagonizing the glucagon receptor can increase the response to insulin in the liver, thereby reducing glucone And reduce liver glucose production. In animal rheumatoid arthritis models, multiple intra-articular injections of IL-1 lead to acute and destructive arthritis (Chandrasekhar et al., Clinical Immunol Immunopathol. 55, 3 82 (1990)). In studies performed on cultured rheumatoid synovial cells, IL-1 is a more potent stromelysin inducer than TNF-α (Firestein, Am. J. Pathol. 140, 1309 85481 -10- 200406399 ( 1992)). Exfiltration of neutrophils, lymphocytes, and monocytes was observed at the local injection site. This exudation is attributable to defamatory chemokines (eg, IL-8) and upregulation of adhesion molecules (Dinarello, Eur. Cytokine Netw. 5, 517-531 (1994)). IL-1 also appears to promote some Viruses play a role in the life cycle. For example, increased expression of HIV by chronic cytokines in chronically infected macrophage cell lines is accompanied by an increase in selective IL-1 production (Folks et al., J. Immunol. 136, 40 (1986)). Beutler et al. (J. Immunol. 135, 3969 (1985)) discussed the role of IL-1 in cachexia. Baracos et al. (New Eng. J. Med. 308, 5 53 (1983)) discussed the role of IL-1 in muscle degeneration. In rheumatoid arthritis, both IL-1 and TNF-oc induce synovial cells and chondrocytes to produce collagenase and neutral protease, which in turn causes tissue destruction in arthritic joints. In arthritic models (rat and mice with collagen rust-induced arthritis (CIA)), the administration of TNF-α in the joints before or after CIA defamation can lead to the accelerated occurrence of arthritis And disease severity (Brahn et al., Lymphokine Cytokine Res. 11, 253 (1992)); and Cooper, Clin. Exp. Immunol. 898, 244 (1992)) ° IL-8 has been found to be involved in multiple diseases Aggravation and / or occurrence, where the infiltration of a large number of neutrophils into inflammation or damage (such as ischemia) is caused by the chemotactic properties of IL-8. These diseases include, but are not limited to: asthma, inflammatory Colorectal disease, psoriasis, adult respiratory depression syndrome, heart and kidney reperfusion injury, thrombosis and glomerulonephritis. In addition to its chemotaxis effect on neutrophils, IL-8 also has the ability to activate neutrophils. Therefore, a decrease in the amount of IL-8 leads to a decrease in neutrophil infiltration. 85481 -11-200406399 There are several ways to block the effects of TNF-oc. One method is to use a TNF-α soluble receptor (such as TNFR-55 or TNFR-75), which has been shown to be effective in animal models of disease conditions caused by TNF-a. The second method is to neutralize TNF-α with a monoclonal antibody specific for TNF-α, cA2. This method shows an improvement in swelling joint counts in rheumatoid arthritis phase II human trials (Feldmann et al., Immunological Reviews, pages 195-223 (1995)). These methods block protein TNF-α and IL-1 by protein sequestration or receptor binding. U.S. Patent No. 5,100,897, attached herein in its entirety, describes a pyrimidinone compound useful as an angiotensin II antagonist in which one of the pyrimidone ring nitrogen atoms is replaced with a substituted phenylmethyl or phenethyl radical. U.S. Patent No. 5,162,325, attached herein in its entirety, describes a pyrimidinone compound useful as an angiotensin II antagonist in which one of the pyrimidone ring nitrogen atoms is replaced with a substituted phenylmethyl radical. EP 48 1448, attached herein in its entirety, describes a p-mylidene compound used as an angiotensin II antagonist, in which one of the ring nitrogen atoms of the ketone ketone is a substituted phenyl, phenylmethyl, or phenyl Ethyl. CA No. 2,020,370, attached herein in its entirety, describes a p-mylide compound used as an angiotensin II antagonist in which one of the p-mylide ring nitrogen atoms is substituted with a substituted biphenyl aliphatic hydrocarbon group . [Summary of the Invention] The present invention includes a new class of compounds for preventing and treating diseases such as diseases caused by TNF-α, IL-1β, IL-6 and / or IL-8 and other diseases such as gout and diabetes. In particular, the compounds of the present invention are useful in the prevention and treatment of 85481-12-200406399 for the treatment of diseases involving inflammation. Because the present invention also includes pharmaceutical compositions containing these compounds, the use of the compounds and compositions of the present invention to prevent and treat diseases (such as inflammation) caused by TNF-a, IL, 'IL_6 and / new_8 Methods, and intermediates and methods for preparing compounds of the invention. The compound of the present invention is represented by the following general formula:

The foregoing merely outlines certain aspects of the invention and is not meant to be, or is understood to, limit the invention. Attached here are all the patents and other announcements mentioned. [Embodiment] According to the present invention, a compound of the following formula is provided

Or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2; R1 is a saturated or unsaturated 5-, 6- or 7-membered ring containing 0, i, 2 or 3 selected from N 'Atoms of G and S', in which this ring can be fused with a benzo group, and 0 is substituted with 0, 1 or 2 oxy groups, in which R1 is again 〇, 丨, 2 or 3 selected from RdKCi. Substituent for alkyl Rd; R2 is Ci6 alkyl 'substituted with 1, 2 or 3 M groups which is substituted with 0, 1 or 2 with' where R2 is not ) Benzyl; and in which _r1_r2 is not 3-benzylhexahydropyridine-i_; and in which if "and 4- are both 4-methylbenzene 85481 • 13-200406399, then -RLR2 is not Hydroxymethyl) hexahydropyridyl; R3 is RC substituted with 0, 1, 2 or 3 substituents selected from Rf &Rd; R4 is 0, 1, 2 or 3 selected from excluding phenylethyl Amino group

Rf & RdW substituent substituted R. ; The prerequisite is that the total number of substituted Re groups on each of R3 and R4 is; R5 is independently H, Cw alkyl or Ci 6 alkyl RC in each case, both are 0, 1, 2 Or 3 substituents selected from Rd; R is in each case independently Cl8 alkyl or Ci6 alkyl Re, both of which are 0, 1, 2 or 3 substituents selected from Rd Substituted; or R6 is Rd; R7 is independently hydrogen, -Cw alkyl or -Cl-4 alkyl RC, wherein any of the preceding carbon atoms is substituted with 0-3 substituents selected from Rd;

Ra is independently Η or Rb in each case;

Rb is in each case independently Cw alkyl, 4-alkyl R. , Each of which is substituted with 0, 1, 2 or 3 substituents independently selected from Rd; -R is in each case independently aryl or saturated or unsaturated 5_, 6_ or 7-membered Heterocycle containing 1, 2 or 3 atoms selected from N, 0 and 3, wherein this ring is linked to 0 or 1 benzo group and 0 or 丨 saturated or unsaturated, 6_ or 7 -A condensed heterocyclic ring containing 1, 2, or 3 atoms selected from N, 0 and 3; wherein any heterocyclic ring is substituted with 0, 1 or 2 oxy groups;

Rd is in each case independently Cw alkyl, quotient, d_4 from alkyl, cyano, -C (= 0) Rf '-C (= 0) 〇Re, -C (= 〇) NRgRg, -C ( = NRg) NRgRg '-0Re, -0C (= 0) Re, -〇C〇〇) NRgRg, -〇C (= 〇) N (Rh) S (= 0) 2Rf -SRe ^ -S (= 0) Rf, .S (= 〇) 2Rf »-S (= 〇) 2NRgRg ^ ^ S (-〇) 2N (Rh) C (= 0) Rf, -S (= 0) 2N (Rh) C (= 0) 0Rf, 85481 -14- 200406399 -S (= 0) 2-N (Rh) C (= 0) NRgRg, -NRgRg, -N (Rh) C (= 0) Re, -N (Rh) C (= 0 ) ORf, -N (Rh) C (= 0) NRgRg, -N (Rh) C (= NRg) NRgRg, -N (Rh) S (= 0) 2Rf4-N (Rh) S (= 0) 2NRgRg;

Re sinks independently in each case is hydrogen or Rf;

Rf is independently Re or Cw alkyl in each case, any of which is substituted with 0-3 substituents, these substituents are selected from -NRgRg, -C (= 0) 0Ri ^ -OR1 ^- N (Ri) C (= 0) Rk ^ -N (Ri) C (= 0) 0Ri ^ -N (Ri) S (= 0) 2Rk '-S (= 〇) nRk, chloro, halogen, -OC1 -4 alkyl groups Rc ,, S (= 0) nCi. 4 alkyl groups Re and Re, wherein any Re in Rf may be further substituted with a CN8 alkyl group or a Cw haloalkyl group;

Rg is in each case independently hydrogen, Re, C ^ o alkyl or -Cw alkyl Rc, each of which is substituted with 0-3 substituents, these substituents being selected from -NR ^ 1 ^ -N (Ri) C (= 0) Rk »-N (Ri) C (= 0) 0Rk ^ -N (Ri) S (= 0) 2Rk, -OR1, -S (= 〇) nRk, cyano, CN8 alkyl and Cw haloalkyl;

Rh is in each case independently hydrogen, Cl.8 alkyl or Cw alkyl Re, each of which is substituted with 0-3 substituents, these substituents being selected from -Nϋ, -N (Rl) C (-〇) Rk, -N (Ri) C (= 0) 0Rk ^ -N (Ri) S (= 0) 2Rk ^ -OR1, -S (= 〇) nRk, cyano, cp8 alkyl, and Cm Haloalkyl; R is Rk or hydrogen; R 疋 Ci-6 alkyl, phenyl or rodyl, V is -N ', -NR5-, -CR6 =, C = 0, C = S or C = NR7; W is -N =, -NR5-, -CR6 =, C = 0, C = S or C = NR7; and X is · N =, _NR5-, -CR6 =, C = 〇, C = S or C = NR7; where -NR5-, C = 0, C = s or C = NR7 represented by v'w and x must be 85481 -15-200406399 〇 or 2; and at least one of V, w and X contains n atom. In another specific embodiment, in conjunction with the above. In any of the following specific embodiments, V is -N =; W is -N = or _cr6 =; and \ is 卞 = or coffee =. In another specific embodiment, in conjunction with any of the above or below specific embodiments, V is c = o 'OS or C = NR7; w ^ cr6 =; and; is regarded as 5_. In another specific embodiment, in conjunction with any of the above-mentioned or the following specific embodiments, CRHCR-, x 疋 C == 〇, c = s or c == nr7. Sub-specific embodiment A: In another specific embodiment, in conjunction with any of the above or the following-specific implementation of M, a saturated or unsaturated 5 ', 6_ or 7_ member containing 0' 1, 2 or 3 A ring of atoms selected from N, 0 and 8, wherein the ring may be fused with a benzo group and substituted with 0, 1 or 2 oxy groups, and wherein ... further with 0, 1, 2 or 3 Substituted by a substituent selected from Rd & Ci.4alkyl "; Sub-specific embodiment B: In another specific embodiment, in conjunction with any of the above-mentioned or the following specific embodiments, R1 is saturated or unsaturated 5-, 5- or 7-membered-a ring containing 1, 2, or 3 atoms selected from N, 0, and 8, wherein the ring may be fused with a benzo group and be bound by 0, 1 or 2 oxy groups And ^ is further substituted with 0, 1, 2, or 3 substituents selected from Rd and cN4 alkyl Rd. Sub-specific embodiment C: In another specific embodiment, in conjunction with the above or the following Any specific embodiment 'R1 is a saturated or unsaturated 5-, 5- or 7-membered ring' containing 1 or 2 copper N atoms and 0 or 1 atom selected from 0 and s, wherein this ring may be connected with Benzo groups are condensed with 0, 1 or 2 oxygen And R1 is further substituted with 0, 1,2, or 3 substituents selected from Rd & Ci-4 alkyl R /. Sub-specific embodiment D: In another specific embodiment, the same as above Or any of the following specific examples, R1 is a saturated or unsaturated 5_, 6_ or 7_ member ring 85481 -16- 200406399, containing 1 or 2 N atoms and 0, 1 or 2 oxo substitutions And wherein Ri is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting of ... and 匚 ·· 4 alkyl ". Second specific embodiment E: In another specific embodiment, in conjunction with any of the above or below specific embodiments, R1 is a saturated or unsaturated 5- or 6-membered ring containing 1 or 2 N atoms . Second specific embodiment F: In another specific embodiment, in conjunction with any of the above or below specific embodiments, 'r1 is a saturated 5- or 6-membered ring containing 1 n atom In another specific embodiment, in combination with any of the above or below specific embodiments, R1 is hexahydropyridine or pyrrolidine. Second specific embodiment Η: In another specific embodiment, in conjunction with any of the above or below specific embodiments, R2 is substituted with 1, 2, or 3 Rd groups and 0 or "solid! ^ (6 Alkyl, which in turn is substituted with 0, i, or: groups, where R2 is not -C (. = 〇) 〇benzyl; and -RLR2 is not 3-benzylhexahydropyridyl; and Wherein when R3 and R4 are both 4-methylphenyl groups, _Ri_R2 is not 4- (light methylmethyl) hexahydro-1: bit-1-enyl. Sub-specific embodiment I: In another specific embodiment, In conjunction with any of the specific embodiments described above or below, R2 is substituted with 1 or 2! ^ Groups and… ... substituted ci6 alkyl groups, which are in turn substituted with 0, i, or 2 Rd groups. Wherein R2 is not -C (= 0) 0 benzyl; and _rLr2 is not 3-fluorenylhexahydropyridyl. Sub-specific embodiment J: In another specific embodiment, in conjunction with any of the above or any of the following In a specific embodiment, R2 is a Gy alkyl group substituted with i, 2 or 3! ^ Groups; and R3 and R4 are not both 4-methylphenyl groups. Sub-specific embodiment K: In another specific embodiment In conjunction with any of the above or below 85481 -17- 200406399, R2 is 1, 2 Cn6 alkyl substituted with 1 ^ group. Sub-specific embodiment L: In another specific embodiment, in conjunction with any of the above-mentioned or the following specific embodiments, R2 is selected from -0Re And · N ^ group, and 0 or 1 1 ^ substituted cN6 alkyl group. Example M · In another specific embodiment, in conjunction with any of the above or below specific embodiments, R2 is -(Cl · 3 alkyl) 0 (Cn5 alkyl) or-(Ci-3 alkyl) -NRgRg 0 specific specific examples N · In another specific embodiment, together with the above or any of the following specific Embodiment, R3 is a sub-specific embodiment substituted with 0, 1, 2 or 3 selected from Rf & Rd. 0: In another specific embodiment, together with the above or the following

The number is 0 or 1.

'Combined with the above or the following halogens and substituents' in conjunction with the above or the following specific examples Q · In any one of the other specific embodiments, R3 is independently selected from 1 or 2 substituted Phenyl. Sub-specific embodiment R. In any one of the specific embodiments, R3 is tea-based. Sub-specific embodiment S. · In another specific embodiment, in conjunction with the above or the following • Any specific embodiment of 18-85481 200406399, R3 is 0, 1, 2 or 3 substituents selected from Rf & Rd A substituted square group, and R is a saturated or unsaturated 5-, 6-, or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from n, 0, and S, wherein the ring is Fused with 0 or 1 benzo group, and 0 or 1 saturated or unsaturated 5-, heart or 7-membered heterocyclic ring containing 1, 2 or 3 selected from N, 0, and S Any one of the heterocyclic rings is substituted with 0, 1 or 2 oxy groups; the former is substituted with 0, 1, 2 or 3 substituents selected from Rf and Rd; the prerequisite is that each The total number of substituted RC groups on R3 and R4 is zero or one. Sub-specific embodiment T: In another specific embodiment, in conjunction with any of the above-mentioned or the following specific embodiments, R4 is 0, i, 2 or 3 selected from those which do not include phenylphenylamino Substitution of Rf & R is a prerequisite that the total number of Re groups substituted on each and the meaning 4 is 0 or 1. Sub-specific embodiment U: In another specific embodiment, in conjunction with any of the above-mentioned or the following specific embodiments, R4 is a saturated or unsaturated 5-, 6-, or 7-membered heterocyclic ring, including 1, 2 or 3 atoms selected from N, 0, and S, where the ring is fused with 0 or 1 benzo group, and 0 or 1 saturated or unsaturated 5_, 6- or 7 -Membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, 0, and S: any of the heterocyclic rings is substituted with 0, 1 or 2 oxy groups; the former is 0 1, 2, or 3 substituents selected from Rf &Rd; a prerequisite is that the total number of substituted groups on each of R3 and R4 is 0 or 1. Sub-specific embodiment V: In another specific embodiment, in combination with any of the above-mentioned or following embodiments, R4 is an unsaturated 6-membered heterocyclic ring containing 1, 2 N atoms. Sub-specific embodiment W: In another specific embodiment, in conjunction with the above or below 85481 -19- 200406399 ^ Specific embodiment ′ R4 is π ratio or p dense. As mentioned above, the above-mentioned specific embodiments and sub-specific embodiments can be used together with other specific embodiments and sub-specific embodiments. The following table is a non-exclusive, non-limiting combination of some specific embodiments:

Specific embodiment VWX R1 R2 R3 R4 1001 -NR5- -N = c = 〇AHNT 1002 -NR5- -N = 〇〇AHNV 1003 -NR 〔-N = c = 〇AHQT 20- 85481 200406399 Specific embodiment VWX R1 R2 R3 R4 1004 -NR5- -N = c = o AHQV 1005 -NR5- -N = c = 〇AHRT 1006 -NR5- -N = c = o AHRV 1007 -NR5- c = o ALNT 1008 -NR5- -N = c = o ALNV 1009 -NR5- -N = c = 〇ALQT 1010 -NR5- -N = c = 〇ALQV 1011 -NR5- -N = c 〇ALR Ding 1012 -NR5- -N = c = 〇ALRV: 1013 -NR5- -N = c 〇AMNT 1014 -NR5- -N = c = 〇AMNV 1015 -NR5- c = 〇AMQT 1016 -NR5- -N = c = o AMQV 1017 -NR5- -N = c = 〇AMRT 1018 -NR5- -N = c = 〇AMRV 1019 -NR5- -N = c = o BHN butyl 1020 -NR5- -N = c = o BHNV 1021 -NR5- -N = c = o BHQ butyl 1022- NR5- -N = c = 〇BHQV 1023 -NR5- -N = c = 〇BHR Ding1024 -NR5- -N = c = 〇BHRV .1025 -NR5- -N = c = o BLN τ 1026 -NR5-- N = c = o BLNV 1027 -NR5- -N = 〇〇 BLQ τ 1028 -NR5- -N = c = o BLQV 1029 -NR5- -N = c = o BLR τ 1030 _ -NR5- -N = c = o BLRV 1031 -NR5- -N = c = o B M N τ 85481 -21-200406399

Specific examples VWX R1 R2 R3 R4 1032 -NR5- -N = c = 〇BMNV 1033 -NR5- c = 〇BMQT 1034 -NR5- -N = c = 〇BMQV 1035 -NR5- -N = 〇〇BMRT 1036- NR5- -N = c20BMRV 1037 -NR5- -N = c = 〇FHNT 1038 -NR5- -N = c = o FHNV 1039 -NR5- -N = c = o FHQT 1040 -NR5- -N = c = o FHQV 1041 -NR5- -N = c = o FHRT 1042 -NR5- c = o FHRV 1043 -NR5- c = op LNT 1044 -NR5- -N = c = 〇FLNV 1045 -NR5- -N = c = 〇FLQT 1046 -NR5- -N = 〇〇FLQV 1047 -NR5- -N = 〇〇FLRT 1048 -NR5- -N = c = 〇FLRV 1049 -NR5- -N = c = o FMNT 1050 -NR5- -N = c = 〇FMNV 1051 -NR5- -N = c = o FMQT 1052 -NR5- -N = c = 〇FMQV J053 -NR5- -N = c = o FMRT 1054 -NR5- -N = c = o FMRV 1055 -NR5- -cr6 = c = o AHNT 1056 -NR5- -cr6 = c = 〇AHNV 1057 -NR5- -cr6 = c = 〇AHQT 1058_ -NR5- -cr6 = c = o AHQV 1059 -NR5- -cr6 = c = o AHRT 85481 -22- 200406399

Specific embodiment VWX R1 R2 R3 R4 1060 -NR5- -cr6 = c = 〇AHRV 1061 -NR5- -cr6 = c = 〇ALNT 1062 -NR5- -cr6 = c = 〇ALNV 1063 -NR5- -cr6 = c = 〇ALQT 1064 -NR5- -cr6 = c = 〇ALQV 1065 -NR5- -cr6 = c = 〇ALRT 1066 -NR5- -cr6 = c = 〇ALRV 1067 -NR5- -cr6 = 〇〇AMNT 1068 -NR5-- cr6 = c = 〇AMNV 1069 -NR5- -cr6 = c = 〇AMQT 1070 -NR5- -cr6 = c = o AMQV 1071 -NR5- -cr6 = c = 〇AMRT 1072 -NR5- -cr6 = c = 〇AMRV 1073 -NR5- -cr6 = c = 〇BHNT 1074 -NR5- -cr6 = c = o BHNV 1075 -NR5- -cr6 = c = 〇BHQT 1076. -NR5- -cr6 = c = 〇BHQV 1077 -NR5- • cr6 = c = o BHRT 1078 -NR5- -cr6 = c = o BHRV 1079 -NR5- -cr6 = c = 〇BLNT 1080 -NR5- -cr6 = c = 〇BLNV .1081 -NR5- -cr6 = c BLQT 1082 -NR5- -cr6 = c = 〇 BLQV 1083 -NR5- -cr6 = c = o BLRT 1084 -NR5- -cr6 = c = 〇BLRV 1085 -NR5- -cr6 = c = 〇BMNT 1086 -NR5-- cr6 = c = o BMNV 1087--NR5- -cr6 = c = o BMQT 85481 -23- 200406399

Specific embodiment V w X R1 R2 R3 R4 1088 -NR5- -cr6 = c = 〇BMQV 1089 -NR5- -CR0 = c = 〇BMRT 1090 -NR5- -cr6 = c 〇BMRV 1091 -NR5- -cr6 = c = o FHNT 1092 -NR5- -cr6 = c = 〇FHNV 1093 -NR5- -cr6 = c = 〇FHQT 1094 -NR5- -cr6 = c = 〇FHQV 1095 -NR5- -cr6 = c = o FHRT 1096- NR5- -cr6 = c = 〇FHRV 1097 -NR5- -cr6 = c = o FLN butyl 1098 -NR5- -cr6 = c = 〇FLNV 1099 -NR5- -cr6 = c = 〇? LQT 1100 -NR5- -cr6 = c = o FLQV 1101 -NR5- -cr6 = c = o FLRT 1001 -NR5- -cr6 = c = o FLRV 1002 -NR5- -cr6 = c = 〇FMNT 1003 -NR5- -cr6 = c = o FMNV 1004 -NR5- -cr6 = c = 〇FMQT 1005 -NR5- -cr6 = c = 〇FMQV 1006 -NR5- -cr6 = c = 〇FMRT 1007 -NR5- -cr6 = c = 〇FMRV .1008 C = 〇-cr6 = -NR5- AHNT 1009 C = 〇-cr6 = -NR5- AHNV 1010 c = 〇-cr6 = -NR5 · AHQT 1011 c = o -cr6 = -NR5- AHQV 1012 c = 〇-cr6 = -NR5- AHRT 1013 -〇〇-cr6 = -NR5- AHRV 1014 c = o -cr6 = -NR5- ALNT 85481 -24- 200406399

Specific embodiment V w X R1 R2 R3 R4 1015 c = 〇-cr6 = -NR5- ALNV 1016 c = 〇-cr6 = -NR5- ALQT 1017 c = 〇-cr6 = -NR5- ALQV 1018 c = 〇-cr6 = -NR5- ALRT 1019 c = 〇-cr6 = -NR5- ALRV 1020 c 〇-cr6 = -NR5- AMNT 1021 c = o -cr6 = -NR5- AMNV 1022 c = o -cr6 = -NR5- AMQT 1023 c = o -cr6 = -NR5- AMQV 1024 oo -cr6 = -NR5- AMRT 1025 c = o -cr6 = -NR5- AMRV 1026 c = 〇CR6 = -NR5- β HNT 1027 c = o -cr6 = -NR5 -BHNV 1028 c = 〇-cr6 = -NR5- BHQT 1029 c = 〇-cr6 = -NR5- BHQV 1030 c = o -cr6 = -NR5- BHRT 1031 c = 〇-cr6 = -NR5- BHRV 1032 c = 〇 -cr6 = -NR5- BLN τ 1033 c = o -cr6 = -NR5- BLNV 1034 c = 〇-cr6 = -NR5- BLQT 1035 c = o -cr6 = -NR5- BLQV .1036 c = o -cr6 =- NR5- BLRT 1037 c = o -cr6 = -NR5- BLRV 1038 c = o -cr6 = -NR5- BMNT 1039 c = o -cr6 = -NR5- BMNV 1040 c = o -cr6 = -NR5- BMQT 1041 c = o -cr6 = -NR5- BMQV 1042 c = o -cr6 = -NR5- BMRT 85481 -25- 200406399

Specific embodiment V w X R1 R2 R3 R4 1043 〇〇-cr6 = -NR5- BMRV 1044 c = 〇-cr6 = -NR5- FHNT 1045 c = 〇-cr6 = -NR5- FHNV 1046 c = 〇-cr6 =- NR5- FHQT 1047 c = 〇-cr6 = -NR5- FHQV 1048 c = 〇-cr6 = -NR5- FHRT 1049 c = 〇-cr6 = -NR5- FHRV 1050 C = 〇-cr6 = -NR5- FLNT 1051 c = o -cr6 = -NR5- FLNV 1052 c = 〇-cr6 = -NR5- FLQT 1053 c = 〇-cr6 = -NR5- FLQV 1054 c = o -cr6 = -NR5- FLRT 1055 c 〇-cr6 = -NR5 -F. LRV 1056 〇〇-cr6 = -NR5- FMNT 1057 c = 〇-cr6 = -NR5- FMNV 1058 c = o -cr6 = -NR5- FMQT 1059 c = 〇-cr6 = -NR5- FMQV 1060 oo- cr6 = -NR5- FMRT 1061 c = 〇-cr6 = -NR5- FMRV In another embodiment, the compound is selected from: 5- (4-chloro-phenyl) -2- [2- (11)- Isopropylamino-methyl)-; 7 Billodium_; [_yl] -3-methyl-6-ρbiyodo-4 -yl-3 Η-p denselyl-4-嗣; 5- (4-Gas-phenyl) -2- [2- (S) -isopropylamino-methyl) -solodine-1_ylb3-methyl-6-ρ -3H- 口 密 Account-4- 嗣; 5- (3-Bromo-phenyl) -2- [2- (isopropylamino-methyl) _ Pyrrolidine_1-kib 3-pyridyl-6-p than yodo-4-yl-3H-p dense bite-4-pyrene; 2- [2- (isopropylamino-methyl) -pyrrolidine -1_yl 3-methyl-6-pyridine-4_yl-26- 85481 200406399 _5- (3-ethylamidino-phenyl) -3H-pyrimidin-4-one; 5- (3- Propyl-phenyl) -2- [2- (isopropylamino-methyl) -ethanoate_ι_yl] -3 -methyl-6-hydrazone-7 pylon-4 -yl-3 hydrazone -p Dense lake-4 -fluorene; 2- [2- (isopropylamino-methyl) -pyrrolidin-1-yl] -3-methyl-6-pyridin-4-yl-5-m-tolyl -3H-p dense lake-4-fluorene; 2- [2- (isopropylamino-methyl) -pyrrolidin-1-yl] -3-fluorenyl-5-fluoren-2-yl-6- Port ratio-4 -yl-3 fluorene-p dense-4-81¾, 6- (2-chloro-ρ bidian-4 -yl) -2- (2-methoxymethylpyridine-1-yl ) -3 · methyl • 5-m-tolyl-3H-pyrimidin-4-one; 2- (2-methoxymethyl-pyrrolidin-1-yl) -3-methyl_6- [2 -(1-phenyl-ethylamino) -pyridin-4-yl] -5-m-fluorenyl-3H-pyrimidin-4-one; 1- (211-hydroxy-propyl) -1'- Methyl-5'-fluoren-2-yl-1,2,3,4,5,6-hexahydro-1 ': "-[4,2'; 4,, 4"] terpyridine-6'- Ketone; 1- (2S-hydroxy-propyl) _1'_methyl-5'-fluoren-2-yl-1,2, 3,4,5,6-hexahydro-1'H · [4,2 '; 4', 4 "] triple p ratio -6'-Pay; 1-(2-Cyclo-2 -methyl- (Propyl) -1'-methyl-5'-naphthalene-2 -yl-1,2,3,4,5,6-hexahydro-ΓΗ- [4,2 '; 4', 4 "] terpyridine _6'_one; isopropyl- [1- (6-tea-2-yl-5-shodo-4-yl-pyrazine-3 · yl) -ρ bihalid-2-ylmethyl] -Amine; 6-[5-(Anaeroylmethyl) p-pyridine-3 -yl] -1 -methyl-3-(2 • naphthyl) -4-(4 -πpyridyl)- Hydropyridin-2-one; 6- [5- (hydroxymethyl) -1- (methylethyl) pyrrolidin-3-yl] -1-methyl-3- (2-fluorenyl) -4- (4-0 than Yodo-based) hydrogen p-bite 2-mesh; 3- (4-Gaphenyl) -6- [2- (hydroxymethyl) pyrrolidinyl] -1_methyl-4- ( 4-pyridine 85481 • 27- 200406399 group) -nitrogen p-pyridine-2 -S is the same, [(1R) -fluorenyl-2- (l'-methyl-5'-naphthalen-2-yl_6'_ Oxy-3,4,5,6,1 ', 6'-hole chloride-2 ratio [4,2'; 4 ', 4 "] terpyridin-1-yl) -ethyl] -aminocarboxylic acid third -Butyl ester; 1-{(211) -amino-3-phenyl-propyl} -1'-methyl-5'-naphthalen-2-yl-1,2,3,4,5,6 -Hexahydro-ΓΗ- [4,2 '; 4', 4 "] terpyridine-6, ketone; 1-{(2R) -isopropyl Phenyl-3-phenyl-propyl} -Γ-methyl-5 '· fluoren-2-yl-1,2,3,4,5,6-hexahydro-1'1 ^ [4,2'; 4 ', 4 "] terpyridine-6, _one; [(13) -benzyl-2- (1'-methyl-5'-fluorene_2-yl-6'_oxy-3,4,5 , 6,1 ', 6'-Hexahydro-2m [4,2'; 4 ', 4 "] terpyridine-1-yl) -ethyl] -aminocarboxylic acid third-butyl ester; 1- {(23) -Amino-3-phenyl-propyl} -1'-methyl-5'-fluoren-2-yl-1,2,3,4,5,6-hexahydro-1'H -[4,2 '; 4', 4 "] terpyridine-6 '· one; 1-{(2S > -isopropylamino-3-phenyl-propyl} -1, methyl-5' -Fluorene-2: yl-1,2,3,4,5,6-hexahydro-1'11- [4,2 '; 4', 4 "] terpyridine-6, -one; {2- [ 3 · (1-methyl-5-fluoren-2-yl-6-oxy-1,6-diargon- [4,4,] bipyridin-2-yl) -pyrrolidin-1-yl] -ethyl Tertiary-butyl aminocarbamate; 6- [1- (2-peryl-propyl) Bihadien-3 -yl] -1-methyl-3 -fan-2_yl-1Η- [4,4 '] bi-pyridyl-2 -fluorene, 6- [1- (2-hydroxy-2-methyl-propyl) -pyrrolidin-3-yl] -1-methyl-3- Fluoren-2-yl-1fluorene- [4,4 '] pyridinyl-2-one; {2- [2- (1-methyl-5-fluoren-2-yl-6-oxy-1,6- Dihydro- [4,4,] bipyridin-2-yl)- Pyridin-1-yl] -ethyltrimethylaminocarboxylic acid tert-butyl ester; 6- [1- (2-amino-ethyl) -pyrrolidin-2-yl] -1-methyl-3 -Stub-2-yl85481 -28-200406399 -1Η- [4,4 '] bipyridyl_2-one; yl-1Η- [4,4'] bipyridyl_2-one; 6_ [ 2- (isopropylamino_methyloxopyrrolidin_ 丨 _ylbuyl__methyl_3_ 荇 _2_yl-1Η-4 [4,4 '] bipyridyl_2 · one; and 3- (4-Gasphenyl) -1-methyl-6_ (2-{[((methylethyl) amino] methyl} pyrrolidinyl) -4- (4-p specific phenyl)) Bite _2_ming. Another aspect of the present invention relates to a pharmaceutical composition comprising the compound of any one of the embodiments described above and a pharmaceutically acceptable carrier. Another aspect of the present invention relates to a method for preventing or treating inflammation, which comprises administering an effective amount of any one of the above-mentioned embodiments. Another aspect of the present invention relates to the prevention or treatment of rheumatoid arthritis in mammals; Pagets disease; osteoporosis; multiple myeloma; uveitis; acute and chronic leukemia produced in the bone marrow; pancreatic beta cell destruction; osteoarthritis Inflammatory rheumatoid spondylitis; gouty arthritis; inflammatory colitis; adult respiratory depression syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; allergy; contact dermatitis; asthma; muscle Degeneration; Cachexia; Reiter's syndrome; Type I and II diabetes; Bone resorption disease; Graft-host response; Alzheimer's disease; Stroke; Myocardial infarction; Ischemic reperfusion injury; Artery Atherosclerosis; Brain injury; Multiple sclerosis; Cerebral malaria; Toxemia; Toxic shock; Toxic shock syndrome—Houqun group; Fever and muscle pain caused by HIV-1, HIV-2, HIV-3, Method for treating cytomegalovirus (CMV), influenza, adenovirus' cancer virus or shingles infection, which comprises administering an effective amount of any one of the above-mentioned embodiments-29- 85481 200406399 Thereof. Another aspect relates to a method for reducing both or TNF-α and IL-1 in plasma, which comprises administering an effective amount of any one of the above specific examples of compounds. Another aspect is a method for reducing the or both of iL-6a and IL-8 in plasma, which comprises administering an effective amount of any one of the compounds of the specific embodiments described above. In another aspect, the method for preventing or treating diabetes in a mammal includes an effective amount of a compound of any one of the above-mentioned embodiments. The second aspect and the third aspect relate to a method for preventing or treating pain in a mammal 'which comprises administering an effective amount of any one of the above-mentioned embodiments. Another aspect of the present invention is a recipe for reducing prostaglandins produced by mammals. The present day includes administering an effective amount of any of the above-mentioned specific embodiment compounds. The method of the present invention is to reduce the activity of mammalian cyclooxygenase by administering an effective amount of any one of the compounds of the above-mentioned embodiments. In a specific embodiment, the cyclooxygenase is COX-2. Another aspect of the present invention is a method for reducing mammalian cyclooxygenase activity. Example: Package: administer an effective amount of the above-mentioned pharmaceutical composition. Yu another-specifically this ribozyme is COX_2. Another aspect of the present invention is a drug containing a compound containing any one of the specific embodiments described above.

I. Manufacture of objects. J Use of Another Compound of the Invention Another 35481 aspect of the present invention relates to the manufacture of a medicament for the treatment of inflammation containing an effective amount of any one of the above-mentioned embodiments. Aspects are related to the manufacture of drugs which are used in the treatment of -30- 200406399

Tumors, uveitis, acute and chronic bone marrow leukemia, pancreatic β-cell destruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory colitis, adult respiratory depression syndrome (ARI) S), Psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis, allergies, contact dermatitis' asthma ', muscle degeneration' cachexia, Reiter's disease, type I diabetes, type II diabetes, bone resorption disease, graft _Host response, Alzheimer's disease, stroke, myocardial infarction, ischemia reperfusion injury, atherosclerosis, brain injury, multiple sclerosis, cerebral malaria, toxemia, toxicemia Shock, toxic shock syndrome, fever 'and muscle pain caused by HIV-1, HIV-2, HIV_3, cytomegalovirus (CMV)' mud-like 'adenovirus, herpes virus or shingles infection method, which includes administering An effective amount of any one of the above-described embodiments. Another aspect of the present invention relates to a method for manufacturing the compound of the above specific embodiment, which includes Ri-R2, wherein Ri contains a secondary ring nitrogen, and

Steps of the reaction. The compounds of the invention may generally have several asymmetric centers and are typically described as racemic mixtures. The present invention includes racemic mixtures, especially racemic-mixtures and separate enantiomers and non-mirror stereoisomers. In the description and patent application of the present invention, "selected from ... and ...," and "is ..." listed species (sometimes called Markush group). In this application 85481 -31 · 200406399 When this language is used in a book, unless otherwise stated, it is meant to include the entire group, or a single member, or any of its sub-members. The use of this language is intended to simplify 'and does not imply the removal of individual elements or sub-groups when needed Unless otherwise stated, the following definitions apply to the words within the scope of the present description and patent application: "Aryl" means phenyl or fluorenyl, where phenyl can be bridged with a c3-4 cycloalkyl "Benyl", whether used alone or in combination, means the bivalent root C4H4 ==, one of which is -CH = CH-CH = CH- when it is linked to another ring in the ortho position That is, a benzene ring is formed, such as tetrahydrofluorene, indene, and the like.

Ca_ (3-alkyl) means an alkyl group containing a to β carbon atoms in a branched, cyclic, or linear relationship or a mixture of any of these three relationships. The so-called alkyl group herein may also contain a double or triple bond. Examples of C1_8 alkyl groups include, but are not limited to:

Halogen and halogen '' means a halogen atom selected from F, ci, Br and I.

Ca-β haloalkyl means the above-mentioned alkyl group, any number of which is at least one and the hydrogen atom attached to the alkyl chain is substituted by F, Cl, Br or I. "Heterocycle '" means a ring containing at least one carbon atom and at least one other atom selected from N, 0 and S. Examples of heterocycles that may appear within the scope of the patents claimed herein include, but are not limited to:

200406399

"Pharmaceutically acceptable salt" means a salt made in a conventional manner and known to those skilled in the art. "Pharmaceutically acceptable salts, including base salts of inorganic and organic acids.'These acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, and oxalic acid. , Tartaric acid, benzoic acid, phenylacetic acid, mandelic acid, and the like. When the compound of the present invention has an acidic function such as a carboxyl group, a suitable pharmaceutically acceptable cation pair of the carboxyl group is skilled in this technology Those who are familiar with the test include soil testing, soil testing, ammonium, quaternary ammonium cations, and the like. For other examples of "pharmaceutically acceptable -33-854S1 200406399 salts", see Berge et al., J. Pharm, Sci. 66 : 1 (1977). Leaving group 4 is "a group that is easily replaced by a nucleophile, such as an amine, stearyl alcohol or alcohol nucleophile. Such leaving groups are well known to those skilled in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimine, and N-benzoyltris. Seated, self-priming, triflate, tosylate and the like. Where appropriate, better leaving groups will be indicated here. "Protecting group" generally refers to the well-known technique used to protect selected reactive groups, such as carboxyl, amine, hydroxyl, hydrogenthio, and the like, from unwanted reactions such as nucleophilic reactions , Electrophilic reaction, oxidation reaction, reduction reaction and similar reactions. Where appropriate, better leaving groups will be indicated here. Examples of the amino protecting group include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenyl, and substituted cycloalkenyl, propyl, substituted propyl, Vinyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples of arylfluorenyl include, but are not limited to, benzyl, n-methylfluorenyl, tribenzylyl, and benzyl, which may be functional groups, alkyl groups, alkoxy groups, hydroxyl groups, and nitro groups, as required. , Acetamidine, acetamidine and the like, and salts such as scales and ammonium salts. Examples of the aryl group include a phenyl group, a fluorenyl group, a phenyl group, a acyl group, a 9- (9-phenylidene group), a phenanthryl group, a dussyl group, and the like. Examples of cycloalkenylalkyl or substituted cycloalkenylalkyl (preferably having 6 to 10 carbon atoms) include, but are not limited to, cyclohexenylmethyl and the like. Suitable fluorenyl, alkoxycarbonyl and aralkyloxycarbonyl groups include fluorenyloxycarbonyl, tertiary-butoxycarbonyl, isobutyloxy, benzyl, substituted phenylfluorenyl, Butyl, ethenyl, trifluoroethenyl, trichloroethenyl, phthalenyl and the like. The protecting group mixture can be used to protect the same amine group of -34- 85481 200406399. For example, the primary amine group can be protected by an aryl group and an aralkyloxycarbonyl group. The amine protecting group can also form a heterocyclic ring with its associated nitrogen, such as ^ 2-bis (methylene) benzene 'xylyleneimine, succinimide, maleimide and Its analogs' and these heterocyclic groups may contain associated aryl and cycloalkyl groups. In addition, the heterocyclic group may be mono-, di-, or tri-substituted, such as nitrophenyl o-dimethylformimine. The amine group can also be protected by forming an addition salt, such as hydrochloride, toluene% acid salt 'difluoroacetate and the like, so as not to cause unnecessary reactions such as oxidation. Most amine protecting groups are also suitable for protecting carboxyl, hydroxy and hydrogenthio groups. For example aralkyl. Alkyl groups, such as tert-butyl, are also suitable for protecting hydroxy and hydrogenthio groups. A silyl protecting group is a silicon atom substituted with one or more alkyl, aryl, and aralkyl groups as necessary. Suitable silyl protecting groups include, but are not limited to, dimethylsilyl, triethylsilyl, triisopropylsilyl, second-butyldimethylsilyl, dimethyl Phenylsilyl, 2-bis (dimethylsilyl) benzene, L2-bis (dimethylsilyl) ethane and diphenylmethylsilyl. Silylation of amine groups can produce mono- or di-silylamine groups. The silylation of an amino alcohol compound can form a team of tris-silyl derivatives. The silyl ear function can be removed by the f silyl ether function using, for example, a metal oxide or ammonium fluoride reagent in a separation step or reaction with an alcohol group in the same step. Suitable silylating agents are, for example, trimethylsilyl chloride, tertiary butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride, phenylmethylsilyl chloride The silylation of amines or their mixed with imidazole or DMF and the removal of silyl protecting groups are well known to those skilled in the art. The methods for preparing these amine derivatives using the corresponding amino acid, aminoamine or amino acid 85481 -35- 200406399 ester are also good at organic chemistry, including amino acid / amino acid ester or amino alcohol chemist Known. The protecting group is removed without affecting the rest of the molecule. This method is known in the art and includes acid hydrolysis, hydrodecomposition and the like. The preferred method includes removal of the protecting group, such as hydrolyzing palladiumoxycarbonyl, with palladium / carbon in a suitable solvent system such as alcohol, acetic acid, and the like or a mixture thereof. The third-butoxycarbonyl protecting group can be removed with an inorganic or organic acid, such as HC1 or trifluoroacrylic acid, in a suitable solvent such as di-alpha or dichloromethane. The obtained amine salt can be neutralized to form a free amine. Carboxyl protecting groups such as methyl, ethyl, fluorenyl, tert-butyl, 4-methoxyphenylmethyl and the like can be removed by hydrolysis and hydrolytic decomposition under conditions well known to those skilled in the art . It should be noted that the compounds of the present invention may contain groups in the form of tautomers, such as cyclic or non-cyclic fluorene and guanidine groups, heteroatom-substituted heteroaryl groups (Y '= 0, S, NR), etc., This is illustrated by the following example:

NHR ·· R

OH 〇

〇 OH

85481 -36- 200406399 Although it is named, described, displayed and / or patented in one form, all forms of tautomers are included in this name, described, displayed and / or patented. Prodrugs of the compounds of the invention also fall within the scope of the invention. A prodrug is an active or inactive compound that is chemically modified after being administered to a patient due to physiological activities in vivo, such as hydrolysis, metabolism, and the like. The suitability and techniques involved in the manufacture and use of prodrugs are well known to those skilled in the art. For a general discussion of prodrugs, including g-targets, see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of masked anion acids include esters such as alkyl (eg methyl, ethyl), cycloalkyl (eg cyclohexyl), aralkyl (eg amidino, p-methoxybenzyl) , And alkylcarbonyloxyalkyl (such as neopentyloxymethyl). Free-state drugs and formaldehyde are explained in vivo by esterase cleavage of amines masked with arylcarbonyloxymethyl substituted derivatives (Bundgaard J. Med. Chem. 2503 (1989)). Drugs containing acidic NH groups, such as Michon, amine acid, and dibutrol, are masked with N-acidoxymethyl (Bundgaard Design of Prodrugs, Elsevier (1985)). The via groups are also masked as esters or ethers. EP 039,051 (Sloan and Little, 4/11/81) discloses a Mannich-iso-isocostal prodrug, its preparation and use. "Cytokine" means a protein secreted that affects the function of other cells, and is particularly related to the modulation of interactions between cells of the immune system or cells involved in the immune response. Examples of cytokines include, but are not limited to, interleukin 1 (IL-1), preferably IL_ip, interleukin 6 (IL-6), interleukin 8 (IL-8), and TNF, and preferably TNF-a (tumor necrosis) Factor-α). "Disease or disease condition caused by TNF, IL-1, IL-6, and / or IL-8" 85481 -37- 200406399 means all disease conditions, of which TNF, IL-1, IL_6, and / or IL -8 or directly such as TNF, IL-1, IL-6, and / or IL-8 alone play a direct role, or secrete another through TNF, IL-1, IL-6 and / or IL-8 Cytokine. For example, IL-1 plays a major role in disease conditions, but the production of this IL-1 is the result of TNF action and can be considered to be caused by TNF.

The compounds of the present invention can be synthesized according to one or more of the following methods. It should be noted that this general method shows the preparation of compounds without specific stereochemistry. However, this method is generally applicable to compounds with specific stereochemistry, such as stereochemistry on the (S) or (R) group. In addition, there is a stereochemical compound (e.g., (R)) which can often be obtained by known methods, such as inversion, to produce a compound with the opposite stereochemistry (i.e., (S)). 4 (3ΗV 口 密 酉 酉 同 ·

When synthesizing 4 (3Η) -pyrimidone 11 (or its tautomer, 4-hydroxypyrimidine), the method shown in Scheme 1 can be used (for this synthesis method, see: DJ Brown, Heterocyclic Compounds: the Pyrimidines, see above). This method involves a cyclization reaction between acrylate XII and pyrimidine V, and then the obtained dihydropyrimidone XIII is oxidized to II. plan 1

85481 -38- 200406399 When synthesizing 2-substituted (4_aminophenyl) -6- (4-pyridyl) _ 'hydroxy-pyrimidine 11 (Wanmu 2) with substituted substituted carbazine, —? Acrylate XII can be used conventionally to condense pyridoxan-4-carboxaldehyde with 4-fluoro

, Glycolic acid, and then esterified. XII can react with various kinds of 脒 V at 咼 temperature. The dehydrogenating agent that converts XII to II is sodium nitrate / acetic acid. Scheme 2 〇

Accordingly, additional compounds of formula II may optionally be prepared using suitable starting materials, where R4 is any other heterocycle as defined by R4. Such starting materials include, but are not limited to, 2-methylpyridine-4-benzaldehyde, 2,6-dimethylpyridin-4-benzaldehyde (Mathes and Sauermilch, Chem. Ber. 88, 1276-1283 ( (1955)), p-quelin-4-carboxylic acid, u-Michido-4-carboxylic acid, 6-fluorenyl yoke bite-4-rebellion, 2-methyl π-methodine_4_ defection, 2,6 -Dimethyl-orally dense-4-amino acid (Bredereck et al., Chem. Ber. 97, 3407-3417 (1964)). The use of 2-nitropyridinecarboxaldehyde results in a derivative of formula II where R4 is 2-nitro-4-pyridyl. Catalytic reduction of nitro group to amine group can produce -39- 85481 200406399 to give 2-amino-4-pyridyl derivative II. The method shown in Scheme 2 is applicable to the use of other ethyl acetate 'to generate compounds of formula II where R3 is a different aryl group. Pyrimidone (IURLH) is reacted with, for example, an alkyl halide such as methyl iodide or ethyl bromide in the presence of a suitable base such as potassium carbonate and the like, and can be substituted with the n-3 position. Option 3

Another method for generating 5,6-diaryl-4-meryl-synthesis (Scheme 3) involves the cyclization of b-metophexyl ester XIV with stone J5L to generate thiouria bites χν. XV can be S-monomethylated to generate XVI. XVI reacts with primary and secondary amines to produce 2-amine substituted 4-hydroxypyrimidines. Although Scheme 3 illustrates the synthesis where R4 is 4-pyridyl, this method is also applicable to other heterocycles within the definition of R4 by using other suitable starting materials. Such starting materials include, but are not limited to, ethyl 2-methylisonicotinate (Efimovsky and Rumpf, Bull. Soc. Chim. FR. 648-649 (1954)) , Methyl 2-methylpyrimidine-4-carboxylate, methyl 6-methylpyrimidine-4-carboxylate, and methyl 2,4-dimethylpyrimidinecarboxylate (Sakasi et al., 85481 -40-200406399

Heterocycles 13, 235 (1978)). Similarly, methyl 2-nitronicotinate (Stanonis, J. Org. Chem. 22, 475 (1957)) can be reacted with aryl acetate, and the resulting β-ketoester and thiourea can be similarly used in Scheme 3 Cyclization. The nitro group is then catalyzed and reduced to an amine group to obtain pyrimidinone II, where R4 is represented by 2-amino-4-tonidyl group (Scheme 4). Option 4

In addition, methyl 2-acetamidinyl isonicotinate (Scheme 5) uses its amine nitrogen as a Chem. Scand. B 42 3 84-3 89 (1988)), tertiary-butyldimethylsilyl group, fluorenyloxymethyl group, benzyl group or the like (P! ) After protection, you can react similar to scheme 3. Option 5

Then, a conventional reagent (for example, tetrabutylammonium fluoride when it is a tertiary-butyldimethyl-silyloxymethyl group) is reacted with the protecting group Pi of the obtained pyrimidine II to produce Pyrimidinone II is obtained, and R4 is represented by 2-acetamido-4-pyridyl. Needless to say, in the method described in Scheme 3, p-fluorophenyl ethyl acetate can be replaced by any 85481 -41-200406399 alkylaryl acetate to make compounds of formula II with different R3 aryl substituents. In yet another method, pyrimidinone II can be prepared by coupling a suitable XVIII derivative (L is a leaving group, such as a pixel root and the like) with a suitable aryl group. 〇

Such aryl / heteroaryl couplings are well known in the art and include the reaction of an organometallic component with a reactive derivative of a second compound, such as a halogen derivative, in the presence of a catalyst. Metal organics can be prepared by reacting metalloaryl compounds with aryl ketones, the aryl portion of which provides a reactive autologous congener, or a reactive 5-pyramidin derivative in the form of a pyrimidone. Therefore, the 5-bromo and 5-iodine derivatives of XVIII (L = Bi ·, I) can be used as arylalkyltin compounds, such as trimethyltin benzene, in an inert solvent such as A palladium catalyst, such as bis (triphenylphosphine) palladium (II) dichloride, is treated in the presence. (Peters et al., J. Heterocyclic Chem. 27, 2165-2173, (1990)) Alternatively, the XVIII halogen derivative can be reacted with, for example, tributyltin sulfanyl chloride, and then lithiated with butyllithium, It is then converted into a trisalbumin tin derivative (L = Bu3Sn) in the presence of a catalyst with an aryl functional compound (Sandosham and Undheim, Acta Chem. Scand. 43, 684-689 (1989). Both methods can be used. Pyrimidine II is formed, in which R11 is represented by aryl and heteroaryl. For example, (Kabbe, Lieb Ann Chem. 704, 144 (1967); German Patent 85481 -42- 200406399 Li 1271 116 (1968)) and Scheme 6 As shown, 5-aryl-2,6-dipyridyl-4 (3H) -pyrimidinone can be used with cyanopyridine and arylacetamidate, such as ethyl phenylacetate, in the presence of sodium methoxide. There is a next step in reaction preparation.

In Scheme 7, the compound of formula XXX of the present invention can be prepared by reacting a methylsulfide intermediate XXXI with an amine NHRR ', for example, heating the mixture at a temperature greater than, preferably 150-210 ° C. Alternatively, a compound of formula XXX can be prepared by reacting a methylsulfonyl intermediate XXXII with an amine NHRR. For example, the mixture is heated at a temperature greater than 40 ° C, preferably 5 (M2 (TC). Scheme 7

XXXI

R XXX

XXXII

Amines of the formula NHRR are commercially available or can be prepared from those skilled in the art using commercially available starting materials. For example, amidine, nitro or cyano can be reduced to the corresponding amine under reducing conditions such as in the presence of a reducing agent such as lithium aluminum hydride. Alkylation and tritiation of amino groups are well known in the art. For palmitic and non-palmyl amines, palmitic amino acids and amidoamines (eg alkyl, aryl, heteroaryl, cycloalkyl, aralkyl, heteroaralkyl, cycloalkyl Alkyl and other substitutions 85481 -43- 200406399

Glycine, β-aminopropionic acid, and the like) are prepared by methods known in the art, such as H. Brunner, P. Hankofer, U. Holzinger, B. Treittinger and H. Schoenenberger, Eur J. Med Chem. 25, 35-44, 1990; M. Freiberger and RB Hasbrouck, J. Am. Chem. Soc. 82, 696-698, 1960; Dornow and Fust, Chem. Ber. 87, 984, 1954; M. Kojima and J. Fujita, Bull. Chem. Soc. Jpn. 55, 1454-1459, 1982; W. Wheeler and D. 05 Bannon, Journal of Labeled Compounds and Radiopharmaceuticals XXXI, 306, 1992; ^ S.

Davies, N. Garrido, O. Ichihara and I. Walters, J. Chem. Soc. 5 Chem. Commun. 1153, 1993 o Lipid Dyes: As shown in Scheme 8, prepare 2 (1H) -pyridone III The pathway includes α, β-unsaturated ketone XXII and sufficient amount of substituted acetamide to crystallize in the presence of a base (El-Rayyes and Al-Hajjar, J. Heterocycl. Chem. 21, 1473 (1984 )), Dehydrogenation in the line.

Scheme 8

85481 -44- 200406399 Option 9

〇ΤγΝΗ2 According to this method (Scheme 9), pyridine-4-carboxaldehyde or other heteroaromatic carboxaldehyde-like pyrimidine-4-carboxaldehyde or quinoline-4-carboxaldehyde can be used with acetamidoaryl and acetamido Aryl or ethyl alkynyl derivatives are reacted at high temperature in the presence of hexahydrop-specific ratio / acetic acid (Bayer and Hartmann, Arch · Parm. (Weinheim) 324, 815 (1991)) and pinazone (CHrCO-qCH3) 3) reacts in the presence of sodium hydroxide to generate unsaturated ketones χχπ (or similar ketones from the corresponding heteroaromatic_4_ carboxaldehyde). XXII reacts with phenylacetamidamine in the presence of sodium ethoxylate to generate 6-substituted 3-phenyl-4- (heteroaryl) of structural formula 111-6 through a ρ ratio of ytterbium. -2 (1Η) -pyridone. In Scheme 10, a feasible method for directing the production of 6-chloro-2 (1Η> pyridone XXIV, a variable intermediate for further modification at the 6-position. This method (G. Simchen, Chem. Ber · 103, 389-397 (1970) is based on the conversion of unsaturated g-cyanocarboxylic acid XXIII into XXIV in the presence of hydrogen chloride. 85481 -45- 200406399 Scheme 10

XXIV reacts with ammonia (Katritzky and Rachwal, J. Heterocylic Chem. 32, 1007 (1995)), and the reaction of primary and secondary amines produces 2-amino-substituted exohydrazone III. In addition, p-pyridone III can be substituted by, for example, reacting an alkyl halide in the presence of a suitable base such as potassium carbonate at the N-1 position. The method for generating the cyclamone of the general formula III is shown in Scheme 11. Option 11

XXVIII XXIX 85481 -46- 200406399 According to this method (Shaw and Warrener, J. Chem. Soc. 153-156 (1958); Hronowski and Szarek, Can. J. Chem. 63, 2787 (1985); Agathocleous and Shaw, J Chem. Soc. Perkin Trans. I, 2555 (1993)), reacting ethoxypropenyl isothiocyanate XXVI with a primary amine to form the addition product fluorenylthiourea XXVII, which is then basic or Cyclization under acidic conditions produces a thiouracil derivative XXVIII, which can be methylated to a methylsulfide derivative XXIX, which is a variable intermediate that undergoes further transformation at the 2-position. The following examples are for illustrative purposes only and must not be considered as limiting the invention to the φ system. Those skilled in the art will understand that the compounds disclosed herein can be modified in various ways without departing from the spirit and scope of the invention. Example Example 1

5- (4-Chloro-phenyl) -2- [2- (R) -isopropylamino-fluorenyl) -p-bilolide-1-yl] -3-methyl-6-P ratio -4 -yl-3 Η -p dense lake -4-嗣 Step 骡 A: 2-((R) -isopropylamino-methyl) -pyrrolidine-1-carboxylic acid tert-butyl ester To the solution of 2. (R) -aminomethyl-pyrrolidine-1-carboxylic acid tertiary-butyl ester 7.72 g in chloroform was added 22.40 g of acetone and 24.54 g of sodium triethoxyalkoxyborohydride. The reaction mixture was heated to 70 ° C for 3.5 hours and then cooled to room temperature. Collected to give the desired product as a pale yellow oil. MS (ES +): 243 (M + H) +. 85481 -47- 200406399 Step B · (R) _Isopropyl · pyrrolidine_2_ylmethyl-amine in 2-((R) -isopropylamino · methyl) _pyrrolidine- 丨 · carboxyl To a solution of 9.12 g of the third tert-butyl acid in methanol, an excess of Hen in diuridine was added. After 30 minutes, the eluent was removed under reduced pressure to obtain the desired product as an off-white solid. MS (Es +): i43 (M + H), step C · 5- (4-chloro-phenyl) -2- [2- (R) -isopropylamino_methylpyrrolidin-1-yl] To a solution of (3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one) (0.46 g of (R) -isopropyl-pyrrolidin-2-ylmethyl-amine) was added 1.00 g of potassium carbonate, Then, 1.07 g of 2-chloro-5- (4-chloro-phenyl) -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one was added at room temperature. After 12 hours, it was collected between chloroform and water and purified by HPLC to give the title compound as a yellow solid. MS (ES +): 438 (M + H) +; (ES-): 436 (M-H), Example 2

5- (4-Chloro-phenyl) -2- [2- (S) -isopropylamino-methyl) βbiloline-butyl 1.3-methyl-6-pyridine-cardiyl- The 3H-pyrimidin-4-one title compound was synthesized in a similar manner to that described in Example 1 using 2- (S) -aminomethyl-pyrrolidine-1-carboxylic acid tertiary-butyl acetate. The resulting compound was a yellow solid. MS (ES +): 438 (M + H).; (ES-): 436 (M-Η). Example 3 85481 -48- 200406399

Br

5- (3-Brexyl-phenyl) -2-chloro-3-methyl-6-t7 Biyodo-4-yl-3H-p dense lake-cardione Step A: In a 500 ml round bottom flask (RBF) Added (3-bromo-phenyl) ethyl acetate (10.3 g, 42.2 mmol), 4-cyanopyridine (4.4 g, 42.2 mmol) and 56 ml of DMF. This mixture was stirred at room temperature under nitrogen. 1 M KOtBu ′ in 42 ml of tBuOH was added dropwise and dropped at room temperature for 1 hour. Methyl isothiocyanate (3.08 g, 42.2 mmol) was added in one portion. Add 100 ml of H20 to stop the reaction. A yellow solid precipitated. After filtration and washing with H2O, 5- (3-bromo-phenyl) -3-methyl-2-methylmethylthio-6-p is obtained as compared to 4--4-yl-3fluorene-. 9.2 g of Myodo-4-one was a gray-yellow powder. MS (ES +): 388 (M + H) +; (ES-): 386 (M-Η). Step B: Add 5- (3-bromo-phenyl) -3-methyl-2-methylmethylthio-6-p than pyridin-4-yl-3H-pyrimidin_4_one to 250 ml of RBF (9.2 g, 23.7 millimoles), 28 ml of Erginaki, and 24 ml of NaOH in 5 N water. The mixture was heated to 85 ° C and stirred for 15 hours. The mixture was cooled to 0 ° C and then neutralized to pH 5 with 1 NHC1 in h20. There was a white solid Shen Dian. After filtration and washing with water, 5.76 g of 5- (3-benzyl-phenyl) -2-acryl-3-methyl-6-eodo-4-yl-3 Hp dense lake-4-one was obtained as White powder. MS (ES +): 358 (M + H) +; (ES-): 356 (ΜΗ) 〇 Step C: Add 5- (3 • bromo-phenyl) -2 • hydroxy-3-formaldehyde to 250 ml of RBF Propyl-6-pyridin-4-yl-3H-pyrimidin-4 · one (5.76 g, 16.1 mmol), 50 ml of POCl3 This mixture was heated to 85 ° C and stirred for 15 hours. Then the mixture was cooled to room 85481-49- / m, and the whole volatile was evaporated to obtain all the volatile # 8, "to form a knife. The obtained black cake was dissolved in dichlorothiazine and NaHC03 for neutralization. Analysis of flash layer After that, 4.72 g of branched chlorine · 3_methyl_6 · chan + yl-3Η- »dense lake-4-one was obtained, as white as the end. Ms (es +): 376 (m + h) +; (es_) : Example 4

Br

5- (3-bromo-phenyl) _2- [2 · (isopropylamino-methyl ^ pyrrolidine small group] _3_methyl-6-ethan-4-yl-3H-p dense lake -4- 酉 Same as 100 ml of RBF (TC under nitrogen with (R) _isopropyl_pyrrolidin-2-ylmethyl-amine (0.78 g, 3.6 mmol) and 50 ml of dichloromethane Add 21 ml of diisopropylethylamine (12 mmol) dropwise, mix for 10 minutes, add 5_ (3_ > odor-phenyl) _2_chloro-3_methyl-6-0 at a time Biyodo_4-yl-3H-. Miyodo-4-one (1.13 g, 3 Emole). This mixture was disturbed at 0 C for 12 hours. The mixture was diluted with 1000 ml of dichloromethane and saturated with Wash with NaHC03 and brine. Purify by flash layer analysis to obtain 1.3 g of the title compound as a gray-yellow solid. MS (ES +): 482 (M + H) + 〇 Example 5

85481 -50- 200406399 2- [2- (Isopropylamino-methyl) _pyrrolidine-pylbutyromethyl-6-pyridyl-5- (3-ethylenyl-phenyl) -3Η -π dense lake-4-one in 250 liters RBF plus 5- (3-bromo-phenyl) _2- [2- (isopropylamino-methyl) -pyrrolidin-1-yl] -3 -Methyl-6-pyridin-4-yl-3H-pyrimidin-4 · one (0.48 g, 1.0¾ mole), 50 ml xylene, 5 mmol # DMF ^ 〇.58 ml tributyl (vinyl) tin. This mixture was purged with nitrogen for one hour. After adding Pd (PPh) 4 (58 mg, 0.05 mmol), the mixture was heated to 14 ° C and stirred under nitrogen for 1 hour. The mixture was cooled to room temperature, 20 ml of a 10% φ KF solution was added, and stirred for 30 minutes. The mixture was diluted with 200 ml of dichloromethane and washed with saturated NaHC03 and brine. After purification by flash chromatography, 028 g of the title compound was obtained as a gray-yellow solid. MS (ES +): 430 (M + H) +; (ES-): 428 (M-H) 〇 Example 6

5- (3-cyclopropyl-phenyl) -2- [2- (isopropylamino-fluorenyl) _pyrrolidin-i-yl] -3-methylpyridin-4-yl-3fluorene- P tightly bite into 100 ml of RBF and add 5- (3-bromo-phenyl) -2 · [2- (isopropylamino-methyl) -pyhalidin-1-yl] -3 -methyl- 6-pyridin-4-yl-3'-pyrimidin-4-one (0.4 g '0.82 mmol), 30 ml of toluene, and cyclopropyl acid (86 mg, 1.0 mmol). The mixture was purged with nitrogen for 1 hour. After adding Pd (pph) 4 (30 mg, 0.025 mmol) and NaOtBu (0.24 g, 2.5 mmol), heat the mixed 85481 -51- 200406399 mixture to 100 ° C and stir under nitrogen hour. The mixture was cooled to room temperature and all volatiles were removed in vacuo. After purification by flash chromatography, 0.1 g of the title compound was obtained as a gray-yellow solid. MS (ES +): 444 (M + H) +; (ES-): 4442 (M-H). Example 7

2- [2- (isopropylamino-methylpyridine_i_yl] _3_methyl-6-p than pyridin-4-yl-5-m -tolyl-3 Η -p dense lake -4-In 100 ml of RBF, add (R) -isopropyl-pyrrolidin-2-ylmethyl-amine (0.13 g '0.6 mmol) at 0 ° C under nitrogen, and 50%. Ml dichloroarsine. Add 0.28 ml diisopropylethylamine (1.6 mmol) dropwise and stir for 10 minutes. Add 2-chloro-3-methyl-6-0 pyridin-4- in one portion. Methyl-5-m-tolyl-3'-pyrimidin-4-one (0.16 g, 0.5 mmol, stirred at 0 ° C for 12 hours. (Mean-methyl chloride intermediate is synthesized similarly to 5 -(3-Bromophenyl) -2-gas-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one) The mixture was diluted with 100 ml of dichloromethane and saturated with NaHC03. Wash with brine. Purify by flash chromatography to obtain 0.219 of the title compound as an off-white solid. Ms (ES +): 418 (M + H) +.

85481 -52- 200406399 2- [2- (isopropylamino-methyl) -pyrrolidine_1_yl] -3-methyl_5_tea_2_yl_6_ _3Η-ρ dense lake-4-net was added (R) -isopropyl_pyrrolidinylmethyl-amine (0.186 g, 0.86 mmol) in 100 ml of RBF at 0 ° C under nitrogen, and 5 0 ml of dichloromethane. 0.3¾ liters of diisopropylethylamine (11.7 mmol) was added dropwise, and stirred for one minute. Add 2-chloro-3 -methyl-5-fluoren-2-yl-6-pyridin-4-yl-3fluoren-pyrimidin-4-one (0.2 g, 0.57¾ mole) once and stir at 0C for 12 hours. (This benzoyl chloride intermediate is synthesized in a similar manner to 5- (3-bromo-phenyl) -2-chloro-3-methyl-6-pyridine · 4 · yl-3pyrimidin-4-one. ) The mixture was diluted with 100 ml of dichloromethane and washed with saturated NaHC03 and brine. After flash chromatography analysis and purification, q · 21 g of title was obtained

Compound as a gray-yellow solid. MS (ES +): 454 (M + K〇 +; 4U (M-H) 〇 Example 9

6- (2-Chloro-exo1: bite-4-yl) -2- (2-methoxymethyl-pyrrolidyl) _3_methyl-5 · πι-tolyl-3Η-ρ dense lake In a 100 ml RBF at 0 ° C, (4-) methoxymethyl-pyrrolidine (0.1 72 g, 1.5 mmol) and 50 ml of dichloromethane were added under a nitrogen atmosphere. Add 0.35 ml of diisopropylethylamine (2.0 mmol) dropwise and stir for 10 minutes. Add chloro-6- (2-chloro ^ biol-4-yl) -3 -methyl-5-m-tolyl-3H_ mouth dense lake 4-one (0.345 g '1.0 millimolar), Stir at 0 ° C for 12 hours. The mixture was diluted with 100 m 85481 -53- 200406399 liters of dichloromethane, and washed with saturated NaHC03 and brine. After purification by flash chromatography, 0.40 g of the title compound was obtained as a gray-yellow solid. MS (ES +): 425 (M + H) +. Example 1 〇

2- (2-methoxymethyl-π-pyrrolidine-1-yl) -3 -methyl-6- [2- (l-phenyl-ethylamino) -pyridin-4-yl]- 5-m-Tolyl-3H-pyrimidin-4-one was added to 100 ml of RBF with 6- (2-chloro-pyridin-4-yl) -2- (2-methoxymethyl-pyrrolidine-1- Methyl) -3-methyltolyl-3H-pyrimidin-4-one (0.3 g, 0.71 mmol), 50 ml toluene, and (S) -a-methylbenzylamine (0.181 ml, 1.42 Emory). This mixture was vented with nitrogen for 1 hour. After adding Pd (OAc) 2 (24 mg, 0.106 mmol), BINAP (65 mg, 0.106 mmol) and NaOtBu (0.191 g, 2.0 mmol), the mixture was heated to 10 (TC and Stir under nitrogen for 3 hours. The mixture was cooled to room temperature and all volatile components were removed in vacuo. After purification by flash layer analysis, 0.18 g of the title compound was obtained as an off-white solid. MS (ES +): 510 (M + H) +. 85481 • 54- 200406399 Option 12 ho2c

CbzCI NH 1,4 · Dioxane 1N NaOH (aq) 0 ° Cto rt 1. SOCI2, Py, THF h〇2C, ^ \ 2. (Me) N (OMe) H2CI -► (Me) (OMe) N ,, NCbz NEt3, DCM, "Ct > z 0 ° C to rt " 3

4

MeMgBr, THF -15 ～ 0 ° C, 1h

NCbz

^ CHO N ^ j, La (OTf) 3 (cat) py ,! hexaargon p ratio 100 ° C, 4h

O py, EtOAc

Cl OMe Q〇 〇q 〇α ΝΗ2Μβ: (Xλ, OMe MeOH, 0 ° C to π, ^, NHMe C 丨, 2h C, * 2 1 1. NHMe ^ d ζ |, 'Ν ^ ΝΗΜβ + | ΙΙ

Me (f ^ reflux for 30 minutes

1.6NHCU, reflux for 3Q minutes 2.MeOH, rt, o / n w

Example 13 λ 85481 55- 200406399 Example 11

W2R-Chinoyl-propylη'-methyl-5, _naphthalene-2.yl. ^^ hexahydro-1 '&[4,2'; 4 ', 4 "] terpyridine-6'-one Step A: Chloro-methoxycarbonylmethyl-pyridinium chloride. In a 250 ¾ liter round bottom flask with a stir bar, add 2-gas methyl acetate (17.5 ml, 0.2 mol), Ethyl acetate (50 ml) and pyridine (16.2 ml, 0.2 mole). The entire homogeneous solution was heated with a condenser at 8 (TC for 24 hours, and the resulting heterogeneous white suspension was cooled to room temperature. , Dust-removed and filtered. The off-white mash was recrystallized with a small amount of ethanol to obtain the title compound (27.4 g, 73%) as a white solid. Ms (ES +): 152 (M), Step B: i-methylamine chloride Formamylpyridinyl_pyridinium pyrene. In a 250 ml round-bottomed flask with a stir bar, salt 1 (25 g, 0.133 mol) was suspended in ethanol (150 ml) at 0 ° C, and the needle was used to The fluorenylamine was passed into the mixture until the whole mixture became homogeneous. The whole yellow solution was stirred at room temperature for 2 hours, and the resulting solution was concentrated to about 30 ml, at which time a large amount of salt 2 appeared. Wash the solid with a small amount of ethanol Salt 2 (21.6 g, 87%) was obtained, which was mainly white crystals. MS (ES +): 151 (M) +. Step C. Hexahydropyridine-1,4-dicarboxylic acid monofluorenyl ester. In a 1-liter round-bottom flask with a stir bar and another funnel, add isocarbamate (13 g, 0.1 mole) 85481 • 56- 200406399, and then add 1,4-dioxane (50 ml). Here To the stirred white suspension was added 5NNaOH aqueous solution (30 ml, 0.15 mol) at room temperature, and the entire nearly homogeneous solution was cooled in an ice-water bath. CbzCl (19 ml, 〇. · 13 moles), this heterogeneous mixture was stirred off at room temperature for 3.5 hours. The resulting mixture was diluted with water (20 ml) and ethyl acetate (100 ml), and ethyl acetate (50 ml X 2 ) The separated layers were extracted. The combined organic layers were washed with brine, dried over MgSCU, and concentrated to give 3 ′ quinacic acid as a typical color oil, which was used directly in the next step without purification. MS (ES +): (M + H) +. Step D: 4- (2-methoxy-propanyl) -benzyl hexahydropyridinecarboxylate. Stirred crude acid 3 in cold (0 ° C) in anhydrous THF (100 ml) The precipitated solution (? Ml) was added to the solution, and then soccl2 was slowly added under nitrogen using a syringe. The resulting white suspension was stirred at the same temperature for 5 minutes, then raised to room temperature and stirred for 2 hours. The homogeneous mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (200 ml). The crude fluorenyl chloride solution was cooled in an ice-water bath, followed by diethylamine (28 ml, 0.2 mol) and Weinreb salt. (10.7 g, 0.11 mole). Allow the entire yellow-orange mixture to warm to room temperature and stir overnight. All mixtures were quenched with water (30 mL) and saturated NaHCO3 (50 mL aqueous solution). The separated aqueous layer was extracted with digas methane (200 mL x ΐ), washed with brine and dried (MgSCU). The whole organic layer was concentrated to obtain the crude product, which was purified by flash chromatography (ethyl acetate / hexane, 1: 2) to obtain the desired amidine 4 (27.8 g, 90% yield, with iso3-piperidine Formic acid), as a gray-yellow oil. MS (ES +): 306 (M + H) +. Step E: 4-Ethylfluorenyl-hexahydropyridine-1-carboxylic acid fluorenyl ester. 85481 -57- 200406399 for stirring

Weinreb amidine 4 (27.83 g, 0.091 mol) in a solution of anhydrous THF (100 ml) at -15 ° C was slowly added to the funnel for 30 minutes. MeMgBr (84 ml, 4 M, in THF / toluene Inside). The resulting heterogeneous mixture was stirred at the same temperature for 30 minutes, followed by 0 N with 1 N HC1 and water (100 ml each). (: Stop the reaction. The separated aqueous layer was extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with water and brine, and dried over MgS04. The solvent was removed by filtration to obtain fluorenyl N_Cbz. Urethane 5 (23 68 g, Dingli), a light-page oil, solidified after standing and used directly in the next step without purification. MS (ES +): 262 (M + H) +. Step F · 4- (3-p-ratio-4-yl-propanyl-gi-yl) -hexahydrop-pyridine benzyl metaborate. Dry with a stir bar and add 5 (30 g, 〇. 11 mol) in a three-necked 1 liter round flask under nitrogen with pyridine (77 ml) at room temperature using a syringe. To this stirred solution A was added 4-pi ratio formic acid (15.4 ml, 0.6 mol). Ear), followed by La (OTf) 3 (7.6 g, 10% aqueous solution). Then hexahydropyridine (11.6¾ liter '0.117 mole) was added dropwise with a syringe, and the resulting brown mixture was heated for 4 hours. The resulting The brown mixture was concentrated under vacuum to remove volatiles, and the residue was diluted with 500 ml of ethyl acetate, washed with saturated NaHC03 aqueous solution and brine, and finally dried on NaeCU. Concentrated as a flash column chromatography Purification (ethyl acetate / hexane, i ·· i to pure ethyl acetate) gave the desired alpha, unsaturated g, 6 (22.1 g '55%) as a grayish yellow solid. ⑽ (ES +): 351 (M + H) +. Step G ·· 1'-methyl-6'-oxy-3,4,5,6,1,6, -hexahydro-211_ [4,2,; 4,4 Triphenylpyridine-1-carboxylic acid phosphonium ester. A 250 ml round bottom flask with a stir bar was charged with phosphonium salt 2 (7.0 g, 0.037 mole) and ester 6 (1312 g, mol). (〇37mol) 85481 -58- 200406399 'This mixture was dissolved in methanol (150 ml). The solution was filled with dimethylamine (40 ° /. Solution in water, 2.4 ml, 〇. 〇19mol). The resulting pale orange liquid was heated to reflux for 45 minutes, and then cooled to room temperature. It was concentrated under reduced pressure and then dried under high vacuum to obtain an orange foam, which was directly diluted with glacial acetic acid (150 ml). It was heated at reflux (oil temperature 12yc) for 4 hours. The solvent η was removed and analyzed by flash column chromatography (2¾ 2 M ammonia methanol in DCM) to give pyridone 7 (11.58 g, 77%) as a grayish yellow Foam. Ms (ES +) ·· 404 (M + H) +. Step Η: 5, bromine-i, _ forma [4,2 '; 4', 4 "] tert-pyridine-1-carboxylic acid benzyl ester. Add to a stirred solution of pyridone 7 (11.58 g '28.7 mmol) in DCM (90 ml) The funnel was slowly charged with a solution of βΓ2 (1.9 ml, 37 mmol) in DCM (20 ml) at -15 ° C under nitrogen over 15 minutes. The resulting yellow heterogeneous mixture was stirred at the same temperature for 30 minutes, and then the reaction was stopped with 25 ml each of Na2S203 (saturated aqueous solution) and NaHC03 (saturated aqueous solution). The separated aqueous layer was extracted with DCM (50 ml x 2), and the combined organic solution sMgSO4 was dried and finally concentrated. Flash column chromatography (2% 2M methanolic ammonia in DCM) gave 3-bromopyridone 8 (9.27 g, 67%) as a yellow foam. ms (ES +): 482 (M + H) + 〇 Step I: 1'-methyl-5, -fluoren-2-yl-6, oxygen_3,4,5,6,1,6,-6 Hydrogen_211_ [4,2 '; 4', 4 "] tert-pyridine-1-carboxylic acid benzyl ester. A stirred 3-bromo 4-pyridone 8 (2.4 g, 5.01 mmol) in a solution of dME (60 ml) with nitrogen for 15 minutes to degas. The entire system was filled with Na2CO3 (2 M aqueous solution, 7.5 ml) using a syringe, and then at room temperature at Under nitrogen, quickly add P (o-tol) 3 (0.18 g, 0.6 mmol), pd (〇Ac) 2 (56 85481 -59- 200406399 mg, 0.25 mmol), and 2-tea S Acid (1.3 g, 7.52 mmol). The whole mixture was sealed and heated at 801 overnight. After cooling to room temperature, the resulting heterogeneous mixture was diluted with water (50 ml) and ethyl acetate (100 ml x 3). ) And DCM (100 mL). The combined organic layers were dried over MgSO and concentrated. The crude material was washed with an ethyl acetate-ether mixture (20 mL each), and the participant 9 was collected as ash Yellow solid (2.56 g, 97%) < 5MS (ES +): 530 (M + H) + 〇 step]: 1- ( 2-foot-hydroxy-propyl) _1, _methyl_5, 荇 _2-yl_1,2,3,4,5,6_ 氲 -1 Η- [4,2,4,4] double υ Pyridone. A yellow suspension of pyridone 9 (1 · 6 g, 0.021 mole) in 6 N HCl (100 ml, diluted with 50 ml of concentrated 1 ^ 1 and 50 ml of water). It was heated to reflux for 30 minutes, and then cooled to room temperature. The resulting homogeneous yellow solution was extracted with ethyl acetate (100 ml x 3), and the separated aqueous layer was neutralized with an aqueous NaOH solution (5 Ν) to about pH 9. The entire aqueous phase was extracted with DCM (150 * l x 3), and the combined organic layers were dried over MgS04, filtered, and concentrated to give the Cbz deprotected product (8.2 g, 95%). A small amount of the crude product ( 80 mg, 0.202 mmol) dissolved in methanol (2 ml) in a sealable tube with a stirrer rod, and (RH +)-propylene oxide (22 μl, 0.3 03¾ Mol) was added with a syringe. Seal, and stir the pale yellow solution at room temperature overnight. After concentration, the resulting mixture was purified by flash column chromatography (8% 2 M methanolic ammonia in DCM) to give the title compound (55 mg, 60%) as Yellow solid. MS (ES +): 454 (M + H) + 1285481-60- 200 406 399

Synthesis of i- (2s'yl_propylmethyl_5, fluoren_2_yl-hexahydro 1 1'1- [4,2 '; 4', 4 "] triplet bite-6, -one. Synthesis The compound was a yellow solid. MS (ES +): 454 (M + H) +. Example 1 3

The fluorene compound is similar to the method described in Example 丨 with + propylene oxide L (2 • hydroxy_2_methyl-propyl) -1, _methyl-5,-hydra_2_yl_1,2, 3,4,5,6-hexaki · 1 '[4,2,; 4,4,4,4] -pyridine-6, -one, t-ton compound was used in a similar manner as described in Example 11 using isobutyl oxide埽 Synthesis. The resulting compound was a yellow solid. MS (ES +) 468 (m + H) +. Example 14

CDI DMF, room temperature

c〇V

NaH, DMSO 0〇Cto

85481 -61-200406399

Isopropyl- [l- (6-Tetra-2-yl-5-p-ratio-4-yl-pyridol-3-ylpyridin-2-ylmethyl] -amine Step A: Naphthalene-2 -Carboxylic acid methoxy-methyl-amidamine. A 250 ml round-bottomed flask equipped with a stir bar was charged with 2-acetic acid (11.23 g, 65.22 mmol), N, N'-carbonyldiimidazole ( 15.88 g, 47.8 mmol), N, 0-dimethylhydroxylamine HC1 (10.27 g, 104.4 mmol) and DMF (100 ml). The resulting solution was stirred at room temperature for 48 hours. The reaction was diluted and washed with 200 ml of 10% HCr. The aqueous phase was extracted with 100 ml of EtOAc. The combined organic phases were washed with saturated sodium bicarbonate solution and then with brine. The organic layer was separated, dried over Na 2 SO 4 and concentrated in vacuo to give 9.29 G of crude product. Purification by flash chromatography (SiO2, 2: 1-1: 1 hexane: EtOAc) gave compound 1 (8.2 g, 58%) as a colorless oil. MS (ES +): 215 (M + H) +. Step B: 1-fluoren-2-yl-2-pyridin-4-yl-ethanone. In a 500 ml round bottom flask equipped with a stir bar, 4-methylpyridine ( 6.7 ml, 68.58 mmol), and then add anhydrous THF (100 ml). The mixture is then cooled -78 ° C, LDA (34.3 ml, 2.0 M in THF) was added dropwise over 5 minutes. After stirring at -78 ° C for 1.5 hours, the compound ι (15 · 5 g, 72 was added dropwise over 10 minutes. • 0 mmol) in anhydrous THF (100 ml). Continue stirring at -78 ° C for 1 hour and then at room temperature for 1 hour. The reaction was diluted with EtOAc, washed with saturated sodium bicarbonate solution, and Wash with brine. Separate the organic layer, dry over Na2S04 85481 -62 · 200406399 'and then concentrate in vacuo to 16.64 g. This crude product is purified by flash chromatography analysis (Si02' 2: 1 EtOAc: hexane-EtOAc) to give the compound 2 (11.70 g, 69%) as a yellow / orange solid. MS (ES +): 247 (M + H) +. Step C: 4-fluoren-2-yl-4-oxo-3-pyridine-4- Ethyl-butyrate. NaH (2.38 g, 56.76 mmol) was added to a 500 ml round-bottomed flask equipped with a drain rod, followed by anhydrous DMSO (100 ml). The reaction mixture was cooled to C 'Stir for 15 minutes. Then add a solution of Compound 2 (11.70 g, 47.30 mmol) in anhydrous DMSO (100 ml) dropwise over 15 minutes using an addition funnel. Stir the heterogeneous solution for 30 minutes Then once Jun ethyl bromoacetate (6.8 mL, 61 mmol · 49), the ice bath was removed. The mixture was stirred overnight and became homogeneous. The resulting solution was poured into saturated ammonium chloride and extracted (EtoAc, 3X). The combined organic layers were washed with saturated sodium bicarbonate, 1.1 H20: brine, and then brine. The resulting organic layer was collected, dried over Na2S04, and concentrated in vacuo to 14.67 g. As a flash layer analysis and purification (SiO2, 2: 1-8: 1 EtOAc: said), compound 3 (3.06 g, 20%) was obtained as a yellow / orange solid. MS (ES +): 333 (M + H), step D. 6-Qin-2-yl-bito-4-yl-4H-pyridazin-3-one. Compound 3 (2.97 g, 8.91 mmol) and t-BuOH (15 ml) were downloaded at > 12 into a 50 ml round bottom flask equipped with a stir bar. To this mixture was added hydrazine (560 microliters '17.82¾ mole)' and the resulting liquid was refluxed overnight. The reaction was concentrated in vacuo 'and heated under vacuum at 125 ° C for 45 minutes. The crude product was purified by flash chromatography (SiO2, 5% MeOH / CH2Cl2) to give compound 4 (2.71 g, quantitative) as a yellow solid. MS (ES +): 301 (M + H) +. Step E: 6-fluoren-2-yl-5_p is more than 4--4-yl-dazin-3-ol. A 85481 -63- 200406399 250 ml round bottom flask equipped with a stir bar was charged with compound 4 (2.71 g, 8.99 mmol) and glacial acetic acid (50 liters). The resulting solution was heated at 95 ° C for 50 minutes. To this mixture was added a solution of Bi * 2 (490 µl, 9.45 mmol) in glacial acetic acid (3 ml). The reaction was stirred at 95 ° C for 1.5 hours and then concentrated in vacuo. To this crude product was added EtoAc (100 ml) and H20 (100 ml). The pH of the aqueous solution was adjusted to about 8 by adding 10% sodium carbonate. The layers were separated and the aqueous layer was extracted (Et0Ac, 3x). The combined organic layers were washed with a saturated sodium bicarbonate solution and then with brine. After drying over Na 2 SO 4, the crude product was concentrated in vacuo to 1.72 g. As a flash layer analysis, purification (Si02, 3% MeOH / CH2Cl2) gave compound 5 (1.37 g, 51%) as an off-white solid. MS (ES +) 299 (M + H) +. Step F: 6-Chloro-3 »• Tetra-2-yl-4 · ^ Biyodo-4-yl-pyridine. A 250 ml round-bottomed flask equipped with a stir bar was charged with compound 5 (1.37 g, 4.58 mmol), tetraethylbutylammonium chloride (1.05 g, 4.651 mmol), and diisopropylethyl Amine (800 μl, 4.59 mmol) and POC13 (20 g). The resulting mixture was heated in an oil bath at 100 ° C for 2 hours and then concentrated in vacuo. P0C13 was removed azeotropically with toluene. The crude material was suspended in EtOAc and iced saturated bicarbonate was added. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with a saturated sodium bicarbonate solution and then with brine. After drying on NajCU, the crude product was concentrated in vacuo to 1.46 g. As a flash layer analysis and purification (Si02, 1% _3% MeOH / CH2Cl2), compound 6 (1.10 g, 76%) was obtained as an off-white solid. MS (ES +): 317 (M + H) +. Step G: Isopropyl- [l- (6-Eth-2-yl-5-P ratio bite-4-yl-sulfur-3-ylpyrrolidin-2-ylmethyl] -amine. In a 2.5 ml microwave tube with a rotating impeller, compound 6 (174 mg, 0.548 mmol) was added, isopropyl_pyrrolidin-2-ylmethylamine 85481-64 · 200406399, hydrochloride (205¾ g, 767 mmol) Ear), diisopropylethylamine (477 µl, 2.7¾ mole) and NMP (0.5 ml). The reaction mixture was heated at 20 ° C in a microwave for 20 minutes and then 220 ° C for 5 minutes. The reaction was diluted with EtOAc 'and washed with 1: 1 saturated sodium bicarbonate · H2O. The aqueous layer was extracted with EtOAc, the combined organic layers were washed with saturated sodium bicarbonate solution, and then washed with brine. The resulting organics were collected in NadCU It was dried over Celite and concentrated to 219 mg in vacuo. Purified by flash chromatography (SiO2, 3% -5% 2 N NH3 MeOH / CHCl3) to give the title compound 7 as a pale yellow solid (0.05 mg, 45%). MS (ES +) · 423 (M + H) + 〇 Example 1 5 6- [5- (hydroxymethyl) pyrrolidinylmethyl_3_ (2_stubyl group)> 4_ (4_pyridyl)- Hydrogenated tonbite-2 -one

Step A. Methyl 4-{(2E) -3- (4-pyridyl) propan-2-yl} -1-benzyl pyrrolidine-2-carboxylic acid ester

To a solution of 4-ethenyl-1-ylpyrrolidine-2-carboxylic acid methyl ester (22.83 g, 0.087 mol) in pyridine was added isonicotinaldehyde (11 ml, 0.11 mol), and 85481 -65- 200406399

La (OTf) 3 (5.2 grams, 0.0087 moles). To this mixture was slowly added hexahydropyridine (7.8¾ liters, 0.079 moles), and the resulting solution was heated at 100 ° C for 4 hours. After cooling, the volatiles were removed and the residue was diluted with EtoAc and washed with water. The combined < extracts were dried, filtered, and concentrated to give the crude product, which was purified by flash chromatography to obtain the title compound (1118 g) as an off-white solid. Step B · Methyl 4- (1βmethyloxy-4- (4-pyridyl) (2-hydropyridyl))-Benzylpyrrolidine-2 · carboxylic acid

The above-prepared unsaturated ketone (11176 g, 0.032 mole) in MeOH (40 ml) was added to the HC1 salt of N-methyl-2-p-pyridylacetamide (7.2 g, 0.038 mole). And dimethylamine (8 ml, 2.0 M in THF, 0.0159 moles). This solution was refluxed for 1 hour and then concentrated. The resulting foam was dissolved in acetic acid (20 ml). The resulting brown was at 120. (: Heated for 4 hours. After concentration, the residue was subjected to flash column chromatography (3% MeOH in DCM) to obtain the title pyridone (8.5 grams) as a 1: 1 non-mirrored stereoisomer Step C · 6- [5- (hydroxymethyl) -1 · benzylpyrrolidin-3-yl] -1-methyl-4- (4-0 specific hydrazine) hydrogenated-p ratio

85481 -66- 200406399 To a solution of the above-mentioned bite ketone (0.8 g, 1.99 mmol) in THF (5 ml) was added slowly at 0 ° C 2 ml of LiBH4 (2.0 M, at THF), after the addition was completed, the mixture was warmed to room temperature for 1 hour 'and refluxed for 1 hour. After cooling, the reaction was stopped with EtOAc and water. The entire mixture was concentrated, extracted with EtOAc, and the extract was dried (Na2S04) and concentrated to give the crude primary alcohol (0.58 g) as a gray-yellow solid, which was used directly in the next step without purification. Step D · 3 -Bromo-6- [5- (Ethylmethyl) -1-ylylpyrrolid-3-yl] -1-methyl

-4- (4-Pyridinyl) -hydropyridin-2-one 0

To a solution of p-pyridone (2.3 g, 6.13 mmol) synthesized in the above in DCM (20 ml) was added saturated NaHC03 and water (5 ml each). The mixture was cooled to 0 ° C and slowly treated with bromine (0.5 ml, 9.2 millimoles) in DCM (5 ml). The resulting heterogeneous mixture was stirred at 0 ° C for another 5-5 hours, then The reaction was stopped with a saturated aqueous NazSzO3 solution. The reaction mixture was extracted (DCM), washed (brine), and dried (Na2SO4). Concentrated and analyzed by column chromatography (5% MeOH in DCM) to give the title compound (1.54 g) as a yellow foam. Step Ε. 6- [5- (hydroxymethyl) -1-epilylpyrrolidin-3-yl] -1-methyl-3_ (fluoren (fluorenyl) -4- (4-pyridyl) hydropyridine -2-one

85481 -67- 200406399 A reaction tube sold was charged with orbitalone (1.0 g, 2.2 mmol), dimethoxy ether (10 ml). Nitrogen was bubbled into the stirred mixture for 10 minutes, and then Pd (OAc) 2 (25 mg, 0.11 mmol), and tri-0-tolylphosphine (81 mg, 0.265 mmol) were added successively. And off acid (0.57 g, 3.31 mmol). The reaction tube was sealed and heated at 80 ° C overnight. After cooling, the whole mixture was filtered through celite and concentrated to give the crude product, which was then purified by flash column chromatography (5% MeOH in DCM) to give the title compound (0.48 g) as a yellow solid. Step F · 6- [5-(# Askylmethyl) pyrrolidin-3-yl] -1-methyl-3- (2-fluorenyl) -4- (4-pyridyl) hydropyridine-2- Ketones and 6- [5- (hydroxymethyl) -1-methyl exo-3-yl] -1-methyl-3 (2-benzoyl) -4- (4-p biphenyl) Hydrogenated p-pylon-2-one. Pd / C (0.32 g) was added to a solution of the above-obtained fluorenylamine (0.32 g) in MeOH (10 ml), followed by formic acid (1 ml). The entire mixture was heated at 50 ° C overnight. After cooling, the resulting mixture was filtered through diatomaceous earth, washed with MeOH, and concentrated to obtain the crude product, which was then purified by flash column chromatography (5% MeOH in DCM) to obtain the desired product (Mg) and amidated product (mg) as a yellow solid. Example 16 6- [5- (¾lmethyl) -1- (methylethyl) p-pylonidyl] -1-methyl-3- (2-fluorenyl) -4- (4-p ratio (Base)-hydrogenated π ratio

85481 200406399 To a stirred solution of amine (50 mg, 0.12 mmol) in dichloromethane (3 ml) was added propidium (18 μl, 0.24 mmol), acetic acid (2 drops) and three Acetyloxy sodium hydride (64 mg, 0.31 mmol). The entire mixture was heated at 50 ° C for 2 hours, then cooled to room temperature, and the reaction was stopped with a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with methane, and the combined organic layers were dried (NajO4), filtered, and concentrated. The crude product was purified by flash column chromatography (MeOH (in DCM)) and the title compound (25 mg) was prepared as a yellow solid. Example 1 7 3- (4-chlorophenyl) -6- [2- (hydroxymethyl) pyrrolidinyl] -1-methyl_4- (4-pyridyl) -hydropyridin-2-one

Step A. 3- (4-chlorophenyl) -1-methyl-6-[(3-oxiranyl-2-ylpropyl) aminopyridyl) -hydropyridin-2-one

6-Amino-3 · (4-Gas-phenyl) -1-methyl-iH- [4,4,] bipyridyl-2-one (prepared in the same manner as described in Example 1) under stirring ( 0.31 g, 1 mmol) in a mixture of DMF (4 ml), pass ν2 for 10 minutes, and then cool to 'successively add 1-bromo-4-epoxypentane (0.2 g, ι · 2 mmol) and NaH (excess). The resulting mixture was stirred at the same temperature for 1 hour, and then the reaction was stopped carefully with saturated aqueous NH4C1 solution and water. The separated aqueous layer was extracted with EtOAc, and the organic layer 200406399 was washed with water and dried (NadO4). Filtration and evaporation gave the crude product, which was purified by flash column chromatography to obtain the title compound (0.37 g) as a yellow solid. Step B. 3- (4-Chlorophenyl) -6- [2- (hydroxymethyl) pyrrolidinyl]-; [mu methylmethyl) -hydrogenated p-pyridin-2-one. In a stirred solution of the epoxy compound prepared above in THF, after cooling to (TC, add NaOH (1 N) aqueous solution 'under nitrogen, heat the resulting solution at 50 ° C overnight, and then cool to Room temperature. This solution was diluted with NHUC1 (aqueous solution), extracted with EtOAc, and the combined organic layers were dried (NajO4), filtered, and evaporated. It was found that the φ purity of the isolated alcohol (0.29 g) was sufficient for the next step Reaction without purification. Example 1 8 [(111) -Methyl-2- (1'-methyl-5'-fluoren-2-yl-6, -oxy-3,4,5,6,1, , 6, _hexahydro-2H- [4,2; 4,4] bipyridin-1-yl) · ethylpyridinecarboxylic acid tert-butyl ester

The inner gas of a round bottom burnt tile with a stir bar dried on a 50 liter furnace was downloaded into {(1R) -benzyl-2-oxo-ethyl-p-tricarboxylic acid tert-butyl ester (6 〇5 gross grams 2.4¾ mole), dry MeOH (10 ml) and 2, methyl-5, fluoren-2-yl 10, 3j, 5, 6-hexahydrodeca is called Qiyi '^ triplex Pyridoxanthinone is 1.2 mg mol). The resulting mixture was stirred at room temperature for 1 hour, then cooled to and NaBH4 (138 mg, 2.6 mmol) was slowly added. This mixture was allowed to cool to room temperature 'and stirred for 1 hour. The reaction was stopped with saturated NaHCQ3 solution and extracted with 85481 • 70- 200406399 DCM (2 x 25 ml). The combined organic phases were washed with water and brine, and dried over sodium sulfate. After removal of the solvent, the crude product was purified by flash chromatography analysis (3% 2 MNH3 / MeOH in DCM) to give the title compound (245 mg) as a yellow solid. MS (ES +): 629 (M + H) +. Example 19 1-{(211) -Amino-3-phenyl-propyl} -1, -methyl-5, fluoren-2-yl-1, 2,3,4,5,6-hexahydro-ΓΗ -[4,2,; 4,, 4 ,,] terpyridine-6, · one

[(1R) -Benzyl-2- (1'-methyl-5, -fluoren-2-yl-6, -oxygen] was downloaded into a round bottom flask equipped with a stir bar and dried on a 50 ml furnace under nitrogen. -3,4,5,6, Γ, 6'-hexahydro-2Η- [4,2 '; 4', 4 ”] terpyridine-butyl) -ethyl] -aminocarboxylic acid tert-butyl Ester (254 mg, 0.4 mmol), anhydrous DCM (10 mL) and trifluoroacetic acid (3 mL), and then stirred at room temperature for 1.5 hours. The mixture was then diluted with DCM and 1 N NaOH. The organic layer was collected, water The layers were extracted with DCM (25 mL). The combined organic phases were washed with water and brine and dried over sodium sulfate. The crude product was purified by flash chromatography analysis (3% 2 M NH3 / MeOH in DCM) to give the title compound (164 mg) as a yellow solid. MS (ES +): 529 (M + H). Example 20 1-{(2R) -Isopropylamino-3.phenyl-propyl} -1'-form -5'-fluoren-2-yl85481 -71 · 200406399 1'2'3,4,5,6_hexahydrodeca [4,2,; 4,4 ,,] terpyridine-6, _ ketone

Download 1 _ {(2R) _amino_3_phenyl_propylbenzene, _methyl_5, tea_2 into a dry bottom-bottomed flask equipped with a stir bar on a 50-liter furnace. -Yl-1,2,3,4,5,6-hexahydro-1,11_ [4,2,; 4,4 ,,] terpyridine-6, _one (124 mg, 0.23 mol Ear), anhydrous MeOH (10 mL) and acetone (68 mg, 1.17 mmol), and then stirred at 50 ° C for 1 hour. After cooling to room temperature, 4 equivalents of triethyl sodium hydride were added, and the mixture was stirred at room temperature overnight. It was then diluted with DCM 'and washed with saturated NaHC03, water and brine, and dried over sodium sulfate. This crude product was purified by flash layer analysis (4% 2 M NH3 / MeOH in DCM) 'to give the title compound (151 mg) as a yellow solid. MS (ES +): 571 (M + H), Example 2 1 [(13) -Benzyl-2- (1, -methyl-5, -fluoren-2-yl-6'-oxy-3,4, 5,6,1 ', 6'-hexahydro-211- [4,2,; 4,4,4,] terpyridyl) -ethyl] -aminocarboxylic acid third-butyl ester

85481 -72- 200406399 The title compound was synthesized in a similar manner to that described in Example 2 using {(IS) -benzyl_2-oxoethylethylaminocarboxylic acid third-butyl ester. The resulting compound was a yellow solid. MS (ES +): 629 (M + H) +. Example 22 1-{(23) -Amino-3-phenyl-propyl} -1, -methyl-5'_fluoren-2-yl-1,2,3,4,5,6-hexahydro -1'11- [4,2 '; 4 ,, 4 ,,] terpyridin-6'-one

nh2 The title compound was prepared in a similar manner to that described in Example 19 using [(1 S) -fluorenyl-2- (1, fluorenyl-5, fluoren-2-yl-6, -oxo-3, 4, 5, 6 , 1,6, -hexahydro-211- [4,2 '; 4', 4 "] terpyridin-1-yl) -ethyl] -aminocarboxylic acid third-butyl ester. The compound obtained is Yellow solid. MS (ES +): 529 (M + H) +. Example 23 Example {(2S) -Isopropylamino-3-phenyl-propyl ^, methyl-5, · fluoren-2-yl -1,2,3,4,5,6-hexahydro-1, fluorene [4,2,; 4,, 4 ,,] terpyridine-6, -one

The title compound was prepared in a similar manner to that described in Example 20 using 1-{(2S) -amino-3- 85481 -73- 200406399 phenyl-propyl} -1'-methyl-5'-fluoren-2-yl [ 4,2 '; 4', 4 "] terpyridine-6, -one Synthesis of MS (ES +): 571 (M + H), Example 24 2,3,4,5,6-Hexahydro-1, only- The obtained compound was a yellow solid {2- [3- (1-methyl-5-tea-2-yl-6-oxo-l 6-η- 夙-[4,4,] bipyridyl-2-yl)- Pyrrolidin-1-yl] -ethyl-bramidate

In 1-methyl-3-fluoren-2-yl-6-pyrrolidin-3_ | _1η_ [4,4,] bipyridyl-2-one such as i, -methyl-5, -naphthalene_2_ 1H- [4,2; 4,4] bipyridine-6'-one, scheme 12, prepared by the method described above (200 mg, 0.52 mmol) in anhydrous CHCl3 (5 ml) To the solution was added nitrogen (2-oxo-ethyl) -carbamic acid tert-butyl ester (209 mg, millimoles) and sodium triacetoxyborohydride (165 mg, 0.1 78 millimoles) and then heated at 80 ° C for 2 hours. After cooling to room temperature, the mixture was diluted with CH2C12 and NaHC03 solution, and the organic layer was collected. The organic phase was washed successively with h20, brine and dried (NadO4). The crude product was purified by flash layer analysis (3% 2 M methanolic ammonia in DCM) to give the title compound (50 mg, 18%) as a yellow solid. MS (ES +): 525 (Μ + Η). Example 25 6- [1- (2-hydroxy-propyl) _pyrrolidin-3-yl] small methyl-3_fluoren-2-yl 85481 • 74 · 200406399 -1H- [4,4 '] bipyridine Keto_2-one

In 1-methyl-3-naphthalene_2-yl-6-saloxol-3-yl-1H- [4,4 '] bipyridyl-2-one (such as the preparation of 1, methyl-5, fluorene -2 · yl], 2,3,4,5,6-hexahydro-l'H- [4,2 '; 4', 4 "] terpyridine-6, _one, scheme 12, prepared by the method ) (0 · 5 φ g '1.3¾ mole) To a solution in anhydrous DMF (5 ml) was added 2-methyl-epoxyethane (2.6 耄 mol, 150 mg), and then heated at 80 ° C. 5 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by flash layer analysis (2% 2M methanol ammonia in DCM) to give the title compound (150 mg, 26%) as a yellow solid. MS ( ES +): 440 (Μ + Η) +. Example 26 6- [1- (2-hydroxy-2-methyl-propyl) -pyrrolidin-3-yl] -1-methyl-3-fluorene-2 -Yl-1Η- [4,4 '] biπ ratio

The title compound was synthesized in a similar manner to that described in Example 25 using 2,2-dimethyl-ethylene oxide. The resulting compound was a yellow solid. MS (ES +): 454 (M + H) +. Example 27 {2 [2- (1-methyl_5-each_2-yl_6-oxy-1,6-dihydro_ [4,4 '] biπ ratio _2_85481 ) Bilodo-1-yl] -ethyl} -aminocarboxylic acid tertiary-butyl acetate

The title compound was prepared in a similar manner to that described in Example 24 using 1-methyl-3-fluoren-2-yl-6- -嗣 Synthesis. The resulting compound was a yellow solid. MS (ES +): 525 (M + H) +. Example 28 6-[1- (2-Amino-ethyl) -0 Biludino-2-yl] -1-methyl-3 -thean-2-yl-1H- [4,4 '] Thanyodo-2- 嗣

Each of {2- [2- (1-methyl-5-tea-2 -yl-6-oxy-1,6-dihydro- [4,4 '] bi-pyridyl-2-yl) A suspension of -1 -yl] -ethyl} -aminocarboxylic acid tertiary-butyl g (100 mg, 0.19 mmol) in a solution of saturated HC1 in EtOAc was stirred at room temperature 4 hour. The title compound was then isolated by filtration and washed with anhydrous EtOAc. MS (ES +): 425 (M + H) +. Example 29 5-Ga-6- [2- (isopropylamino-methyl) -pyrrolidin-1-yl] -1-methyl-3-fluoren-2-yl-1hydrazine- [4,4 '] Bipyridyl-2-one 85481 -76- 200406399

Bu Yinba · N-methyl-2-naphthalene 2-yl-ethylamine

A mixture of tri-2-ylethyl acetate (42.8 g, 200 mmol) and 64 ml of methylamine (40% by weight in η20) was stirred at room temperature overnight. Then the white precipitate was decanted and washed with water. The title compound was obtained after vacuum drying as a white solid. MS (ES +): 226 (M + H) +. Step B: 3-hydroxy-N-methyl-3-pyridin-4-yl-acrylamide

N-methyl_2-fluoren-2-ylacetamidine (94 g, 470 mmol) and 71.3 g (71¾ liter) of ethyl isonicotinate (47 mmol) were dissolved in portions Equipped with a mechanical stirrer's temperature probe and 500 ml into a funnel in a 3 liter 3-neck round bottom flask with 800 ml of anhydrous THF. The flask was cooled to 0-5 in an ice-water bath. 〇. To this heterogeneous mixture was slowly added tBuOK (1 M, 470 in THF, 470 ml) and 70, and the resulting heterogeneous yellow-brown mixture was stirred at room temperature overnight. Cool the dark drops to the heart 5 in an ice-water bath. 〇. Add distilled water (800 mL). This alkaline solution was neutralized to pH 7 with 37% HC1. The solvent was removed in vacuo at room temperature. The resulting solid was filtered off and washed with water (1 liter) and toluene (1 liter). The suspension / premix was filtered. The obtained solid was dried under vacuum at 50 ° C overnight, and the crude product 85481-77-200406399 was directly used in the next step. Step C: 6-amino-1-methyl-3-naphthalene-2_yl-1 '-[4,4,] bipyridyl-2-one

Add 3-Chloro-N-methyl-2-fluoren-2-yl-3-eodo-4-yl-propionamine (15.2 g, 50 mmol), NCCH2COOH (8.51 g, 100 mmol) Ear), NH4HC03 (15.8 g, 200 mmol) and AcOH (12.01 g, 11_4 ml, 200 mmol) were dissolved in batches with a mechanical stirrer, temperature probe and Dean-Stark trap 500 ml of toluene in a 1 liter 3-neck round bottom flask. The reaction was refluxed at 120 ° C for 72 hours, and then the solvent was removed in vacuo. Add water (100 ml) and EtOH (100 ml). This acidic solution was tested with 5 N NaOH to pH 12. The resulting dark solution was refluxed at 90 ° C for 2 hours, and the solvent was evaporated. Add dichloromethane (DCM) (100 mL). This alkaline solution was acidified to pH 1 with 37% hci. The aqueous layer was slowly neutralized with NH4OH to pH 7-8. A precipitate formed at pH 5. The resulting suspension was stirred for 小时 hours, the solids were filtered off and washed with toluene. Dry under vacuum at room temperature overnight to give the title compound as a yellow solid. MS (ES +): 428 (M + H) + 〇 step D5,6-dichloro-1_methyl-3-fluoren-2-yl-1fluorene- [4,4,] bipyridyl_2 - steel

Anhydrous copper (11) (1_2 eq.), Tertiary butyl nitrite (15 eq. 85481 • 78- 200406399) and anhydrous (Η / N (40 ml)) were placed under nitrogen with a stir bar. A 100-ml two-necked round-bottomed flask dried on the furnace. The resulting suspension was heated to 40 ° C, and 6.amino-1-methyl_3_ 荇 _2-yl_111- was slowly added. [4,4,] bipyridyl-2-one (0.5 g, 1.53 mmol) while stirring. Keep heating at 40 ° C for 20 minutes, cool the reaction to room temperature, and stop with 2 N HC1 The reaction was extracted with DCM (3 X 150 mL). The combined organic phases were washed with water and brine, and dried over magnesium sulfate. The solvent was removed to give a pale yellow solid. MS (ES +): 381 (M + H) +. Step E : 5-chloro-6- [2- (isopropylamino-methyl) _pyrrolidin-1-yl] -1-methyl-3 -naphthalene-2-yl-1Η- [4,4 '] Dipyridyl-2-Lang was charged in a microwave tube with 5,6-dichloro-1-methyl-3-methyl-2-yl-1H- [4,4,] bipyridyl-2-one ( 0.300 g, 0.8 mmol), diisopropylethylamine (2 equivalents) and isopropyl-pyrrolidin-2-ylmethyl-amine (1 equivalent). This heterogeneous suspension was microwaved Within 150 ° C Heat for 10 minutes. The resulting brown suspension was dissolved in DCM and analyzed by ISCO combiflash system with 97 / 3DCM / MeOH as flash layer to obtain the title compound. MS (ES +): 487 (M + H) +. Example 30 6 -[2- (isopropylamino-methyl) -pyrrolidin-1-yl] -1-methyl-3-fluoren-2-yl-1fluorene-4 [4,4 '] bipyridyl-2 -ketone

5-Chloro-6- [2- (isopropylamino-methyl) -pyrrolidin-1-yl] -1-methyl-3-fluoren-2-yl-1fluorene- [4,4 '] Bipyridyl-2-one (0.200 g, 0.41 mmol), 85481 -79- 200406399 1-4-dioxane (10 ml) and Raney nickel (1. · 7 weight ratio) under nitrogen Inside a 100 ml round bottom flask equipped with a stir bar. The resulting suspension was heated at 90 ° C for 30 minutes. After cooling to room temperature ', the mixture was filtered through celite to remove the solvent. The crude product was purified by ISCO combiflash system with 97/5 DCM / MeOH / NH3 as flash layer to obtain the title compound. MS (ES +): 453 (M + H) 4 *. Example 3 1 3- (4-chlorophenyl) -1-methyl-6- (2-{[((methylethyl) amino] methyl} pyrrolidinyl) -4- (4-pyridyl) Pyridin-2-one

Slowly add DMSO (0.14 ml, 1.94 mmol) to a solution of a stirred solution of chloramphenicol (23 ml, 0.259 mmol) in DCM (2 ml) at -78 ° C. Stir for 10 minutes. , 3- (4-chlorophenyl) -6- [2- (hydroxymethyl) pyrrolidinyl] -1-methyl-4- (4-pyridyl) hydropyridine-2-one was added dropwise via a leak tube. (Example 17) A solution of (51 mg, 0.129 mmol) in DCM (2 ml), and the resulting solution was stirred at -78 ° C for another 20 minutes. The entire solution was treated with Et3N (0.31 ml, 2.26 mmol) and then slowly heated to 0 ° C for 40 minutes. After dilution with water, the separated aqueous layer was extracted with DCM, and the combined organic layers were washed with brine and dried over NadO4. Filter and evaporate to obtain the crude corresponding aldehyde. Dissolve it in chloroform (5 ml), and mix with isopropylamine (0 ·; [ml, U9 mmol), acetic acid (2 drops), and triacetoxyl. Sodium borohydride (014 g, 0.65 mmol) was mixed. The entire mixture was heated to 50 ° C for 1 hour, diluted with NaHC03 (aqueous solution), and cooled to room temperature. The separated aqueous layer was extracted with DCM, and the combined organic phases 85481 -80-200406399 were dried (Na2S04) and filtered. The solvent was removed under reduced pressure to give the crude product, which was purified by flash chromatography (5% MeOH in DCM) to give the title compound. As a yellow solid. Biological identification The following identification is used to determine the ability of the compounds of the present invention to inhibit the production of TNF-α and IL-1-β. The second identification can be used to determine the inhibition of TNF-α and / or IL-1-β by oral administration of test compounds to mice. The third identification, the in vitro identification of glucagon binding inhibition, can be used to determine the characteristics of the compounds of the present invention in inhibiting glucagon. The fourth identification, the inhibition activity of cyclooxygenase (COX-1 and COX-2) in vitro, can be used to determine the properties of the compounds of the present invention to inhibit COX-1 and / or COX-2. Fifth identification, Raf-kinase inhibition identification, can be used to determine the properties of the compounds of the present invention to inhibit MEK phosphorylation by activating Raf-kinase. Identification of lipopolysaccharide-activated monocyte TNF production Isolation of monocytes The ability of test compounds to inhibit the production of TNF by monocytes activated by bacterial lipopolysaccharide (LPS) in vitro was evaluated. Fresh residual source leukocytes (a by-product of platelet removal) were obtained from the local blood bank, and peripheral blood mononuclear cells (PBMCs) were isolated by density gradient isolation using Ficol-Paque Plus (Pharmacia). PBMCs were suspended in DMEM at a density of 2 X 106 / ml. This DMEM was supplemented with 2% FCS, 10 mM, 0.3 mg / ml glutamic acid, 100 units / ml phonomycin G, and 100 mg / ml streptomycin sulfate ( Complete medium). The cells were placed in a Falcon flat-bottomed 96-well culture dish (200 microliters / concave) and cultured overnight at 37 ° C and 6% CO2. Wash with 200 μl / well fresh medium unless adherent cells. Adherent cells (approximately 70% mononuclear 85481 -81-200406399 cells) were supplemented with 100 microliters of fresh medium. Preparation of test compound stock solution The test compound was dissolved in DMZ. Compound stock solutions were prepared at a starting concentration of 10-50 μM. Dilute the stock solution to 20-200 μM before complete medium. Each compound was then made into nine two-fold serial dilutions in complete medium. Cells were treated with test compounds and TNF production was activated with lipopolysaccharide. 100 microliters of each test compound dilution was added to a microtiter well containing adherent monocytes and 100 microliters of complete medium. Monocytes were cultured with the test compound for 60 minutes, during which 25 microliters of complete medium containing 30 ng / mL of E. coli K532 lipopolysaccharide was added to each well. The cells were cultured for another 4 hours. Then, the culture supernatant was taken out, and the amount of TNF in the supernatant was measured by ELISA. TNF enzyme-linked immunosorbent assay (ELISA) A flat bottom 96 concave Corning High Binding ELISA plate was coated with 150 μl / concave 3 μg / ml of mouse anti-human TNF-oc MAb (R & D Systems # MAB210) overnight ( 4 ° C). Then use 200 μl / concave with 20 mg / ml BSA (standard ELISA buffer: 20 mM, 150 mM NaCl, 2 mM 0 & (: 12, 0.15 111) ^ thimerosal,? 117.4) without & (: 12 The ugly 1 ^ 13 eight buffer solution was blocked at room temperature for 1 hour. The dishes were washed and supplemented with 100 microliters of test supernatant (diluted to 1 ·· 3) or standard solution. The standard solution consisted of 11 parts 1 · A 5-fold serial dilution of 1 ng / ml recombinant human TNF (R & D Systems) stock solution. The dishes were incubated on an orbital shaker (300 rpm) at room temperature for 1 hour, washed, and washed with 100 Microliter / concave was supplemented with 4: 1 ratio of biotinylated 0.5 μg / ml goat anti-human TNF-oc (R & D Systems # AB-210_NA). The dish was cultured for 40 minutes 85481 -82- 200406399 and washed , Supplemented with 100 μl / concave 0.02 μg / ml alkaline phosphatase-conjugated streptavidin (Jackson ImmunoResearch # 016-050-084). Incubate the dish for 30 minutes, wash, and use 200 μl / Concave 1 mg / ml p-nitrophenyl phosphate supplement. After 30 minutes, read the disc on a Vmax disc reader at 405 nm. Data analysis Substitute the standard curve data into the second grade Formula, by solving this equation to find the concentration to measure the unknown TNF-α concentration from its optical density (OD). Then make a graph of the TNF concentration and the concentration of the test compound by a second-order polynomial. Then use this equation to calculate the TNF production Reduce the concentration of the test compound by 50%. The compounds of the present invention have also been shown to inhibit the release of IL-Ιβ, IL-6 and / or IL-8 by monocytes mediated by LPS, which is well known to those skilled in the art It was found that the concentration of IL-1β, IL-6 and / or IL-8 was determined by the method. In a similar manner to the above-mentioned identification of TNF-a released from monocytes induced by LPS, the compounds of the present invention have also been shown to inhibit the induction by LPS Monocytes release IL-1β, IL-6 and / or IL-8, which is known by measuring the concentrations of IL-1β, IL-6 and / or IL-8 by methods known to those skilled in the art Therefore, the compound of the present invention can reduce the increased amount of TNF-a, IL-Ιβ, IL-6 and IL-8. Reducing this increased isoinflammatory cytokine to a basic amount or below is beneficial to control and slow down the disease And relieve many diseases. All these compounds can be used to treat TNF-a, IL-1β, IL-6 and IL-8. A disease caused by TNF-a. Identification of TNF production by lipopolysaccharide-activated THP1 cells THP1 cells were resuspended in THP1 medium (RPMI 1640, 10% heat-inactivated FBS, 1XPGS, 1XNEAA, plus 30 μΜ βΜΕ) The concentration is 1E6 / 85481 -83-200406399 ml. Place 100 microliters of cells per well on a polystyrene 96-well tissue culture dish. 100 microliters of bacterial LPS per recess was made with THP1 medium and transferred into the recess. The test compound was dissolved in 100% DMSO and diluted three-fold in a polypropene 96-well microtiter dish (drug dish). HI control and LO control recess contain only DMSO. Transfer 1 microliter of test compound and 10 microliters of LPS from the drug dish to the cell dish. The treated cells were induced to synthesize and secrete TNF-a at 37 ° C for 3 hours. Transfer 40 μl of conditioned medium into 110 μl of ECL buffer (50 mM Tris-HCl pH 8.0, 100 mM NaC, 0.05% Tween 20, 0.05% NaN3, and 1% FBS) plus 0.44 nM MAB610 monoclonal Ab (R & D Systems), 0.434 nM ruthenium AF210NA polyclonal Ab (R & D Systems) and 44 μg / ml / goat anti-mouse M280 Dynabeads (Dynal) in a 96 concave polypropylene dish. After 2 hours of incubation at room temperature with shaking, the reaction was read on an ECL M8 Instrument (IGEN Inc.). On the ruthenium-based TNF-α immune complex, in the presence of TPA (Origlo's active ingredient), the use of low volts leads to a periodic redox reaction at 620 nM. The amount of TNF-a secreted in the presence of the compound is compared with that secreted in the presence of only the DMSO vehicle (HI control), calculated using the formula:% control (POC) = (cpd-mean LO) / (mean HI-average L0) * 100. The data (consisting of POC and inhibitor concentration μM) was substituted into the 4-parameter equation (y = A + ((BA) / (l + ((x / C) AD))) using the Levenburg-Marquardt nonlinear regression formula, where a is the minimum y (POC) value, B is the maximum y (POC) value, 'C is the internal point x (cpd concentration), and D is the slope factor). The following compounds show activity in THP1 cell identification (LPS-induced TNF release) with IC50 of 20 μM or less: 5- (4-chloro · phenyl) -2- [2- (R) -isopropyl Amino-methyl)-? Pyrrolidine-1-yl] -3- 85481 -84- 200406399 methyl-6-p than methyl-4-yl-3H-. Miyodo-4_ 嗣;, yl] -3, 5- (4-chloro-phenyl) -2- [2- (S) -isopropylamino-methyl) -t-methyl-6-0 Biyodo-4-yl_3H-p dense lake-4-fluorene; 5- (3-bromo-phenyl) -2- [2- (isopropylamino-methyl) _pylidene] 3 -6 ^ Biyodo-4-yl-3 hafnium-p dense 4-copper; 2- [2- (isopropylamino-methyl) -πbihyo-1-yl] -3- Methyl-6-t? Specific bite-4-yl-5- (3-vinyl-phenyl) -3H-pyrimidin-4-one; 5- (3-cyclopropyl-phenyl) -2- [ 2- (isopropylamino-methyl) -pyrrolidin-1-yl] -3-methyl-6_pyridine_4_yl-3H_pyrimidin_4_one; 2- [2- (isopropyl Aminoamino-methyl) -pyrrolidin-1-yl] -3-methyl-6-pyridin-4-yl-5-m-tolyl-3H-pyrimidin-4-one; 2- [2- (Isopropylamino-methyl) -p-pyrrolidine-1 -yl] -3-methyl-5-naphthalen-2-yl-6-leafyl-4-Hydroxy-4 -Sun; 6- (2-chloro-pyridin-4-yl) -2- (2-methoxymethyl-pyrrolidin-1-yl) -3-methyl-5-m-tolyl-3Η -π dense bite-4-one; 2- (2-methoxyfluorenyl_pyrrolidin-1-yl) -3-methyl-6- [2- (l-phenyl-ethylamino) · Pyridine-cardiyl] -5-m-tolyl-3H-pyrimidin-4-one; 1- (211-hydroxy-propyl) -1'_methyl-5'-fluoren-2-yl-1 2,3,4,5,6-Hexahydro-1 '± [4,2'; 4 ', 4 ”] terpyridine-6, -one; 1- (2S-hydroxy-propyl) -1'_ Methyl-5'-stub-2.yl-1,2,3,4,5,6-hexahydro • 1'11- [4,2 '; 4', 4 "] terpyridin-6'_one ; 1- (2-hydroxy-2-methyl-propyl) -1, _methyl-5'-fluoren-2-yl-1,2,3,4,5,6-hexahydro-1'11 -[4,2 '; 4,4,4,] terpyridine-6, -one; isopropyl- [1- (6-tea-2-yl-5-0 -3-ylpyridine-2-yl 85481 -85-200406399 methyl] -amine; 6- [5- (hydroxymethyl) salrolidin_3-yl] + methyl-3- (fluorenapyryl ) _4_ (4w than pyridyl) -hydropyridin-2-one; 6- [5- (Ethylmethyl) -1- (methylethyl) said pyridin-3-yl] _ 丨 · methyl_ 3_ (2-naphthyl) -4- (4-ρ specific octyl) -hydrogenated bispyridin-2-one; 3- (4-chlorophenyl) -6- [2- (hydroxymethyl) pyrrolidine [] Yl] _1-methyl_4_ (4_pyridyl) -nitride p-bide-2-left; [(111) -fluorenyl-2- (1'-methyl-5'-fluoren-2-yl -6, oxygen-3,4,5,6,1,6, hexaki-2H- [4,2; 4,4] two commands dian_yl) _ethyl] _aminocarboxylic acid Tri-butyl ester; 1-{(211) -amino-3-phenyl-propyl} -1, -methyl-5, fluorene-2_ Radical _1,2,3,456_ hexahydro-1'11- [4,2 '; 4', 4 ”] triplet E-6_, identical; 1-{(2R) -isopropylamino- 3-phenyl-propylbutanyl 1, methyl-5, tris-yl-1, 2,3,4,5,6-hexahydro-1,11_ [4,2,; 4,4 ,,] Terpyridine-6, ketone; [(1S) 4ylmethyl ^ yl ^^ from hexahydro-211- [4,2 '; 4', 4 ''] triplexyl)-ethylamino Tert-butyl acetic acid; {{2S) -amino-3-phenyl · propyl H, -methyl-5, hexahydro-1'1 ^ [4,2 '; 4', 4 ”] terpyridine_6, _one; 1-U2S) -isopropylamino-3-phenyl-propyl group], _ methyl_5, _fan_2_yl-1,2,3 , 4,5,6-ττ hydrogen_1 '; "-[4,2'; 4''4"] terpyridine_6, _one. {2-[3-(1-甲 墓 -5-奈-2 -yl-6-oxy-1 6-> "/ 1 j, 1,6--lice- [4,4,] bipyridyl-2-yl) -pyrrolidin-1-yl] -ethyl Tert-butylaminocarboxylic acid 6- [1- (2-Cyclo-propyl) _ mouth-to-mouth bite_3-tampering] _1_methyl-3-fluorene_2_yl 85481 -86-200406399 -1Η- [4,4 '] bipyridyl-2-one; 6- [1- (2-Cycloyl-2-methyl_propyl) -pyloridin_3-ylbutan-1 _Methyl_3_tea_2yl-1Η- [4,4] biπ ratio Yl-2-fluorene; {2- [2- (1-methyl-5-fluoren-2-yl-6-oxy-1,6-dihydro- [4,4,] bipyridyl-2-yl)- Pyrrolidin-1-yl] -ethyl} -aminocarboxylic acid third-butyl ester; 6- [1- (2-amino-ethyl) _pyrrolidin-3-yl] -1-methyl- 3_steam_2yl-1Η- [4,4 '] bi-ratio than stilbene-2- 嗣; 5-chloro-6- [2_ (isopropylamino-methyl) -ηBiloxidyl ι_methyl_3_dichloro-2-yl-1Η- [4,4 '] bipyridyl-2-one; 6- [2- (isopropylamino-methyl) -pyrrolidin-1-yl] _ι_methyl_3 • tea_2_yl-1Η- [4,4] bi-p-ratio-2-yl; and 3- (4-chlorophenyl) -1-methyl-6- (2_ {[((Methylethyl) amino] methyl} t-xanthenyl) -4- (4 ^ pyridinyl) hydropyridin-2-one. Inhibition of murine LPS-induced TNF-α production was administered to mice as lipopolysaccharide (2 mg / kg, intravenously) 30 minutes before injection in male DBA / 1LCJ mice or test compounds in the vehicle (the carrier was composed of 〇3 N HC1 Made of 0.5% tragacanth gum). Blood was collected 90 minutes after LPS injection, and the amount of TNF_a in the serum was analyzed by ELISA. In animal models of inflammation, including carageenan paw edema, collagen-flavored arthritis, and adjuvant arthritis, such as the carageenan paw edema model (C · A · Winter et al Proc · Soc · Exp · Biol · Med · (1962) vol 111 pp. 544; K. F. Swingle, in RA Scherrer and MW Whitehouse, Eds., Anti-inflammatory Agents, Chemistry and Pharmacology, Vol. 13-11, Academic, New York, 1974, p. 33) 85481 87-200406399 and collagen-induced arthritis (D. E. Trentham et al J. Exp. Med. (1977) vol. 146, p. 857; J. Courtenay, Nature (New Biol.) (1980) Vol. 283, p. 666), the compounds of the invention show anti-inflammatory properties. CHO / hGLUR cells were used for 125 I. glucagon binding screening. This identification is found in WO 97/16442, which is attached for reference. Reagents Reagents can be prepared as follows: (a) Preparation of fresh 1 M oxa-diazaphenanthrene (A1 (11 ^ 11) (198.2 mg / ml ethanol); 〇) Preparation of fresh 0.5

(Sigma); (c) Protease Inhibitor Mix (1000 ×): Add 5 mg leuprotease peptide, 10 mg benzamidine, 40 mg bacitracin and 5 mg soybean trypsin inhibitor per ml of DMSO, and store in whole portions. -20 ° C; (d) 250 μM human glucagon (Peninsula): 0.5 mg vial dissolved in 575 μl 0.1 N acetic acid (1 μl in the identification of non-specific binding yields a final concentration of 1 μM ) 'Stored at -20 ° C in whole parts; (e) Identification buffer: 20 mM Tris (pH 7.8), 1 mM DTT, and 3 mM diazaphenanthrene; (f) Identification buffer with BSA ( For dilution labeling only; 0.01% identification final concentration): 10 μl BSA (heat-inactivated) and 990 μl identification buffer; (gfl glucagon (NEN 'receptor grade, 2200 curie / milliliter) Moore): Dilute to 50,000 counts per minute / 25 microliters of BSA-containing identification buffer (final final concentration of approximately 50 pM). IlL take CHO / hGLUR for identification and sprint 1. Take out from the confluence flask The culture medium was washed once with PBS (Ca-free, Mg-free) and enzyme-free dissociation solution (Specialty Media, Inc.) 2. Add 10 ml of enzyme-free dissociation solution and store at 37 ° C for about 4 minutes. 3 · Gently knock off the cells, grind, take whole numbers and count, and centrifuge the rest at 10085481-88 · 200406399 rpm for 5 minutes. 4. Resuspend the pellets in the identification buffer, 75000 per 100 microliters Cells can be prepared with the same volume of CHO / hGLUR cell membrane instead of whole cells. The final protein concentration of the membrane preparation is determined on a batch basis. Identification of glucagon binding inhibition can be determined by assaying 125I-pancreas in the presence of a compound of formula I The reduction of glucagon is performed. The reagents are combined by the following method: Compound / carrier 250 μM glucagon 5 Ι-Teng glucagon CHO / hGLUR total cell binding-5 microliters-25 microliters 100 microliters + compound 5 microliters Liter /--25 microliters 100 microliters non-specific binding-/ 5 microliters 1 microliter 25 microliters 100 microliters The mixture was incubated on a 275 rpm shaker at 22 ° C for 60 minutes. Mixing was useless Innotech Harvester or Tomtec Harvester was filtered through a pre-soaked (0.5% polyethylimine (PEI)) GF / C filter pad and washed four times with ice-cold 20 mM Tris buffer (pH 7.8). Gamma-scintillation counter Measure the radioactivity of the filter. Compounds of the present invention also inhibit glucagon binding to the glucagon receptor. Cyclooxygenase activity identification The human mononuclear leukemia cell line, TP-1, is characterized by exposure to COX-1 phorbol ester only; human osteosarcoma cell line 143B mainly expresses COX-2. 85481 -89-200406399 TTP-1 cells were routinely cultured in RPMI complete medium, this medium was supplemented with 10% FBS, and human osteosarcoma cells (HOSC) were cultured with 10% fetal bovine serum (MEM-10% FBS). Minimum required medium; all cell cultures were performed at 37 ° C in a humid environment containing 5% CO2. COX-1 identification For COX-1 identification, TPP-1 cells were seeded to confluence and divided 1: 3 into RPMI, containing 2% FBS and 10 mM phorbol 12-myristate 13-acetate ( TPA) and incubated on a shaker for 48 hours to prevent adhesion. The cells were transformed into pellets and suspended in Hank's buffer (HBS) at a concentration of 2.5 X 106 cells / ml, and placed in a 96-concave culture dish at a density of 5 X 105 cells / ml. The test compound was diluted with HBS, added at the final required concentration, and the cells were cultured for an additional 4 hours. Add arachidonic acid to a final concentration of 30 mM, and incubate the cells at 37 ° C for 20 minutes. The enzyme activity was measured by the following method. Identification of COX-2 For identification of COX-2, sub-conjugated HOSC trypsin digestion was performed and suspended at a concentration of 3 X 106 cells / ml in MEM-FBS containing 1 ng of human IL-1 b / ml. The density of 3 × 104 cells per recess was placed in a 96-concave tissue culture dish, cultured on a shaker for 1 hour to make uniform, and then statically cultured for 2 hours to make adhesion. The medium was then replaced with MEM containing 2% FBS (MEM-2% FBS) and 1 ng of human IL-lb / ml, and the cells were cultured for 18-22 hours. After replacing the medium with 190 ml of MEM, 10 ml of the compound diluted in HBS was added to the required concentration and the cells were cultured for 4 hours. The supernatant was removed and replaced with MEM containing 30 mM arachidonic acid. The cells were cultured at 37 ° C for 20 minutes, and the enzyme activity was measured by the following method. 85481 -90- 200406399 COX activity measurement After culturing with arachidonic acid, the reaction was stopped by adding 1 N HC1, then neutralized with 1 N NaOH, and centrifuged to pellet cell debris. The commercially available ELISA (Neogen # 404110) was used to determine the PGE2 concentration to measure the cyclooxygenase activity of HOSC and THP-1 cell supernatants. Calibration was performed using the PGE2 standard curve, and commercially available COX-1 and COX-2 inhibitors were used as standard controls. Raf kinase identification Raf kinase activity in vitro is measured by matrix MEK (Map kinase / ERK kinase) to determine the degree of phosphorylation of activated Raf kinase, as described in GB 1,238,959 (as attached). Phosphorylated MEK was entrapped with a filter and the radiolabeled salt salt was quantified by scintillation counting. MATERIALS: Activated Raf was produced by Sf9 transfection with baculovirus with Raf, val12-H-Ras, and Lck expressing "Glu-Glu" -epitope. The "Glu-Glu" -epitope, Glu_Try-Met-Pro-Met_Glu, was fused to the carboxyl end of the full-length c-Raf. The catalytically active MEKΓκ97A mutation) was generated from Sf9 cells transfected with K97A MEK1 baculovirus expressing the c-terminal "Glu-Glu" -epitope. Anti- "Glu-Glu" antibodies were purified from cells grown as follows: Grussenmeyer, et al., Proceedings of the National Academy of Science, U.S.A. page 7952-7954, 1985. Column buffer = 20 mM Tris pH 8, 100 mM NaCl, 1 mM EDTA, 2.5 mM EGTA, 10 mM MgCl2, 2 mM DTT, 0.4 mM AEBSF, 0.1% -91-85481 200406399 η-octyl leaf glucosamine , 1 nM okadeic acid, and benzamidine, leupeptin, gastric inhibitory peptide, and aprotinin each 10 ug / ml 0 5x reaction buffer: 125 mM HEPES pH = 8, 25 mM MgCl2, 5 mM EDTA, 5 mM Na3V04, 100 μg / ml BSA. Enzyme dilution buffer = 25 mM HEPES pH 8, 1 mM EDTA, 1 mM Na3V04, 400 μg / ml BSA.

Stop solution: 100 mM EDTA, 80 mM sodium pyrophosphate. Filter plate: Millipore multi-function sieve # SE3M078E3, Immobilon-P (PVDF). method:

Protein purification: Sf9 cells were infected with baculovirus, and seeded as described in Williams, et al., Proceedings of the National Academy of Science, U.S.A. page 2922-2926, 1992. All subsequent steps are done on ice or at 4 ° C. The cells were made into pellets and lysed by ultrasonic in column buffer. The lysate was spun at 17,000 xg for 20 minutes and then filtered through a 0.22 micron. The protein carrying the epitope was purified by chromatography on a GammaBind Plus affinity column. This column was coupled to a "Glu-Glu" antibody. The protein was loaded on the column, washed with two column volumes of column buffer, and washed with 50 μg / ml Glu-Tyr-Met-Pro-Met-Glu in the column buffer.

Raf kinase identification: Test compounds were evaluated in ten 3-fold serial dilutions starting from 10-100 μM. Add 10 microliters of test inhibitor or control dissolved in 10% DMSO to the identification dish, and add 30 microliters containing 10 microliters of 5x reaction buffer, 1 mM 33P-γ-ΑTP (20 microcurie / ml ), 0.5 μl of MEK (2.5 mg / ml), 1 μl of a mixture of 50 mM β-thioargonyl ethanol. The reaction was started by adding 10 μl of an enzyme dilution buffer containing 1 mM 85481 -92- 200406399 DTT and an activated Raf that produced linear kinetics within the reaction time. The reaction was mixed and incubated at room temperature for 90 minutes. 50 microliters of stop solution was added to stop the reaction. Transfer 90 microliters of whole stop solution to GFP-3 0 cellulose microtiter filter dishes (Polyfiltronics), wash the filter dishes in four concave volumes of 5% phosphoric acid, allow them to dry, and then add 25 microliters of scintillation mixture (Cocktail). 33Pγ radiation was counted using a TopCount Scintillation Reader. Other compounds that can be made include: #

85481 93- 200406399

85481 -94- 200406399

85481 95- 200406399

The "dissolvable" compound of the present invention can be administered as the only active pharmaceutical agent, but it can also be used in combination with a plurality of compounds of the present invention or other agents. When the combination is given, the oral therapeutic agent can be formulated into separate compositions at different times or at different times, or the therapeutic agent can be given as a single composition to f. The above description is only an illustration of the present invention, and it should not be considered that the present invention is limited to the disclosed compounds. Those skilled in the art can also make various changes within the scope and nature of the present invention, which is defined within the scope of patent application. Those skilled in the art can easily determine the main features of the present invention from the above description, and can make various changes and modifications to the present invention for various uses and conditions without departing from the spirit and scope thereof. For the treatment of diseases, cancer, and / or hyperglycemia caused by TNF-α, IL-1β, IL-6 and IL-8, the compounds of the present invention can be administered orally, parenterally, inhaled, rectum 'or locally in dosage units. The formulation is administered, which contains conventional pharmaceutically acceptable carriers, adjuvants, and carriers. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrasternal administration or intraperitoneal administration. 85481 -96- 200406399 The treatment of diseases and disorders herein also includes prophylactic administration of a compound of the present invention, a pharmaceutically acceptable salt or pharmaceutical composition thereof, to a patient (ie, an animal, preferably an Mammals, preferably humans) to treat diseases such as pain, inflammation, and the like. ^ The doses of the diseases, cancer, and / or hyperglycemia caused by the compounds and / or the compositions of the present invention, IL-6 and IL_8 depend on 10,000; various factors, including diseases ^ {, the age and weight of the patient , Gender, health status, and severity of disease, route of administration, and specific compounds used. Household caterpillars can vary widely in dosage, and are determined based on conventional standards. The dose used in the method disclosed herein is about 0.01¾ to 30 mg per kg of body weight per day, preferably about 0.01 mg to 10 mg / kg, and more preferably about 0.25 mg to 1 mg / kg. The pharmaceutically active compound of the present invention can be prepared into a pharmaceutical agent according to the Pharmacy Law for administration to patients, including humans and other mammals. For oral administration, the pharmaceutical composition may be, for example, in the form of a capsule, tablet, suspension, or liquid. The pharmaceutical composition is preferably formulated in the form of a dosage unit ' For example, this formula may contain the amount of active ingredient: 1 to 2000 mg, preferably about 1 to about mg, more preferably about 5 to 150 ¾ g. The appropriate dose to humans or other lactating animals may vary greatly depending on patient conditions and other factors, but it can still be determined by the f-gauge method. The active ingredient may be administered by injection as a composition with a suitable carrier, including saline, dextrose or water '. The daily parenteral dose is 〇2 ::? Body weight, preferably about. .1 to about ⑽ 0-25¾ grams to 1 mg / liter. 85481 -97- 200406399 Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be formulated with suitable dispersing or wetting agents and suspending agents according to the known method. Such a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Useful vehicles and solvents include water, Ringer's solution, isotonic sodium chloride solution. In addition, sterilized fixed oils can be used as solvents or suspension media. For this purpose, any blended solid oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables. Suppositories for rectal administration of the drug can be combined with suitable non-irritating excipients, such as coconut oil and polyethylene which can be liquid at normal temperature but liquid at the rectal temperature and can melt in the rectum and release the drug. Alcohol, prepared by mixing. A suitable topical dose of the active ingredient of the compound of the present invention is 0.1 mg to 150 mg, and it is administered one to four times a day, preferably one or two times a day. When used for local α 卩, the active ingredient may contain a formulation of 0.001% to 10% weight / weight, such as 1% to 2% by weight, but may also contain up to 10% by weight, Better not more than 5. /. The weight ratio is more preferably from 01% to 10/0 of the formulation. Formulations suitable for topical administration include liquid or semi-liquid preparations (e.g., lotions, lotions, creams, creams or pastes) suitable for permeation through the skin and drops suitable for administration to the eyes, ears or nose. For administration, the compounds of the invention are generally mixed with one or more adjuvants suitable for the route of administration. These compounds are compatible with lactose, sucrose, starch, cellulose alkanoates, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of scale acid and sulfuric acid, gum arabic, gelatin, alginic acid Sodium, polyethylenic acid _85481 -98-200406399 slightly, and / or polyethylenic alcohol, mixed and then made into tablets or capsules to identify the ^ ^ €. Alternatively, the compound of the present invention can be dissolved in physiological saline, ... glycol, propylene glycol, ethanol, corn oil, peanut oil, cottonseed oil, polyethylene, tragacanth, and / or various buffers. Other adjuvants and administration of sesame oil are well known. Carriers and diluents may include time-delay materials, glycerol monostearate, or glyceryl distearate, which may be used alone or in combination with other materials known in the art. These pharmaceutical compositions can be made in solid form (including granules, particles, or substrates) or liquid forms (e.g., solutions, suspensions, or emulsions). These pharmaceutical compositions can be used in conventional medical procedures' such as reducing bacteria and / or containing conventional adjuvants, such as preservatives, stabilizers, moisturizers, emulsifiers, buffers and the like. Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose, or starch. These dosage forms may also contain substances other than inert diluents, such as lubricants such as magnesium stearate, under normal operation. For capsules, tablets, pills, this dosage form can also contain buffering agents. Tablets and pills can also be prepared with casing. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and inert diluents containing water commonly used in the art. Such compositions may also contain adjuvants such as wetting agents, sweeteners, flavoring agents', and fragrances. 85481 -99-

Claims (1)

200406399 Scope of patent application: • A compound of the following formula Or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2; R1 is a saturated or unsaturated 5-, 6-, or 7-membered ring containing 0, i, 2 or 3 selected from N , 0 and S atoms, in which the ring may be fused with a benzo group, and is substituted with 0, 1 or 2 oxy groups, wherein Ri is again 0, i, 2 or 3 selected from RdKCw alkane R2 is substituted by a substituent of group Rd; R2 is a Cm alkyl group substituted with 1, 2 or 3 1 ^ groups and 0 or a group, which is substituted with 0, 1 or 2 1 ^ groups, wherein R2 is not a -C (100) 〇 + group, and -rW is not a hexafluoroethanyl group; and if R3 and R4 are both 4-methylphenyl groups, -RLR2 is not a 4- (hydroxymethyl Radical) hexahydro exyl; R3 is Rc substituted with 0 '1' 2 or 3 substituents selected from r / and Rd; R4 is 0, 1, 2 or 3 selected from excluding -phenyl Re substituted with 1 ^ and 1 ^ substituents including ethylamine; the prerequisite is that the total number of substituted Rc groups on each R3 & R4 is 0 or i; R5 is independently Η in each case , Cw alkyl or Cu alkyl Re, both of which are substituted with 0, 1, 2 or 3 substituents selected from Rd; R6 in each case Li is a group Cn8 alkyl or Cl 6-R. , Both are substituted with 0, 1, 2 or 3 substituents selected from Rd; or meaning 6 is! ^; 85481 200406399 R7 is independently hydrogen, -C 1-6 alkyl or -Cw alkyl r. , Whose carbon atom is substituted with (M substituents selected from Rd; any one of Each one is 0,1, amidino, ReiCw alkyl R. RC with 2 or 3 substituents independently selected from Rd, which in each case are independently aryl or saturated or unsaturated 5-, 6- or 7-membered, containing 2 or 3 options Heterocyclic ring of atoms from N, 0 and 3, where this% is 1, 2 with 0 or 1 benzo group and 0 or 1 saturated or unsaturated 5-, 6- or 7-membered Or 3 heterocycles fused from N, 0 and S atoms; where any heterocycle is substituted with 0, 1 or 2 oxy groups; Rd is in each case independently Cm alkyl, halo, Cm Haloalkyl, cyano, -C (= 0) Rf, -C (= 0) 0Re, _c (= 〇) NRgRg, -C (= NRg) NRgR§ '-ORe, _〇c (= 〇) Re , -〇C (= 0) NRgRg, -0C (= 0) N (Rh) S (= 0) 2Rf ^ -SRe ^ -S (= 0) Rf ^ -S (= 0) 2Rf, -S (= 0) 2NRgRg '-S (= 0) 2N (Rh) C (= 0) Rf, -S (= 0) 2N (Rh) C (= 0) 0Rf, -S (= 0) 2-N (Rh) C (= 0) NRgRg, -NRgRg '-N (Rh) C (= 0) Re, -N (Rh) C (= 0) 0Rf, N (Rh) C (= 0) NRgRg, -N (Rh) C (= NRg) NRgRg, -N (Rh) S (= 0) 2R% il -N (Rh) S (= 〇) 2NRgRg; Re is independently hydrogen or Rf in each case; Rf in each case Independently is C 1 · 8 alkyl, any of which is substituted with 0-3 substituents. The substituent is selected from -NRgRg, -0 (= 0) 0 ^ J -OR '^ ^ ^ (^) 0 (= 0) 0 ^, 85481 -2-200406399 -N (ϊ ^) 3 (= 0) 2Ι ^, -S (= 0) nRk, cyano, function, -〇Ci-4 alkyl Rc, -spokcm alkyl Rc and Rc, any of Rc may be further substituted by Ci-8 alkyl or Chd alkyl Rg is in each case independently hydrogen, Re'Ci-IG alkyl or -Ci.4 alkyl Rc, each of which is substituted with 0-3 substituents, these substituents being selected from -Nϋ , -N (Ri) C (= 〇) Rk 5 -N (Ri) C (= 0) 0Rk ^ -NCRjspOhRk, -OR1, -S (= 〇) nRk, cyano, CN8 alkyl and Cw haloalkyl Rh is in each case independently nitrogen, Ci-8fluorenyl or Ci.4alkyl. , Each of which is substituted with 0-3 substituents, these substituents are selected from -NR #,-called 1 ^) (: (= 0) 01 ^, -N (Ι0 (: (= 0) 0ί ^, -NCRbspOhRk, -OR1'-S (= 0) nRk, cyano, Ci.8alkyl and Cm_fluorenyl; R ^ Rk or hydrogen; alkyl, phenyl or benzyl; V is -N =, _NR5-, _CR6 =, C = 0, OS or ONR7; W is -N =, _NR5-, -CR6 =, C = 0, C = S or C = NR7; and X is -N =, -NR5 -, _CR6 =, C = 0, C = S or C = NR7; where -NR5-'C = 〇 represented by V'W and X, C = S or C = NR7 total number of groups must be 0 or 2; And at least one of v, W, and X contains an N atom. 2 · The compound according to item 1 of the scope of the patent application, wherein R · is an aryl group substituted with 0, 2 or 3 substituents selected from Rf and Rd And R4 is a saturated or unsaturated 5_, & or 7_ membered heterocyclic ring containing 1 ′ 2 or 3 atoms selected from N, 0, and 8, wherein the ring is linked to 0 or H85481. -3-200406399 benzoyl fused, and 0 or 1 saturated or unsaturated 5-, 6- or 6-membered heterocyclic ring containing 1, 2 or 3 selected from N, 0 and S Atom; any heterocyclic ring is 0,1 2 oxo substituted; the former is substituted with 0, 1, 2 or 3 substituents selected from Rf and Rd; a prerequisite is that the total number of rc group substitutions on each R3 and R4 is 0 or i. 3. The compound according to item 2 of the scope of patent application, wherein: V is -NR5 ;; W is -N = or -CR6 =; and X is 〇〇, 〇S or C = NR7. 4. According to the scope of patent application Compound of item 3, wherein R2 is a Cw alkyl group substituted with 1 or 2 Rd groups and 1 1 ^ group, and it is substituted with 0, 1 or 2 Rd groups, wherein R2 is not -C (= 0) 0 fluorenyl group; and -R ^ R2 is not 3- fluorenyl hexahydropyridin-1-yl. 5. The compound according to item 1 of the scope of patent application, which is selected from: 5- (4- Chloro-phenyl) -2- [2- (11) -isopropylamino-methyl) _pyrrole-1-yl] -3-methyl-6 · ^ is denser than yodo-4-yl-3 Yodo-4- 嗣; 5- (4-chloro-phenyl) -2- [2- (S) -isopropylamino-methyl) _pyrrolidine_boxy] -3-methyl-6 -p than Yodo-4-yl dense bite-4- 嗣; 5- (3-bromo-phenyl) -2 · [2- (isopropylamino-methylpylidene] methyl-6- Pyridin-4-yl-3H-pyrimidin-4-one; 2- [2- (isopropylamino-methyl) -pyrrolidin-1-yl] -3-methyl-ratio 5- (3-Ethylfluorenyl-phenyl) -3′-pyrimidin-4-one; 5- (3-cyclopropyl-phenyl) -2- [2- (isopropylamino-methyl ) Bilodynyl] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -4- 85481 200406399 2- [2- (isopropylamino-methyl) ) -ΡBilodo-1 -yl] -3 -methyl-yl-5 -m-methylbenzyl-3 Η -p dense bite 4-嗣, 2- [2- (isopropylamino- (Methyl) -pyrrolidin-1-yl] -3-methyl-5-fluoren-2-yl-6-exo-b-dodyl-4-yl-3Η-ρ dense lake-4- 嗣; 6- (2- Chlorhidolide-4-yl) -2- (2-methoxymethylpylide-I-yl) -3 -methyl-5-m-tolyl-3 p · p dense lake · 4 · 嗣; 2- (2-methoxymethyl-pyrrolidin-1-yl) -3-methyl-6- [2- (l-phenyl-ethylamino) -pyridin-4-yl] -5- M-tolyl_3H-pyrimidin-4_one; 1- (211-hydroxy-propyl) _1'-methyl-5'-fluoren-2-yl-1,2,3,4,5,6_ Hexahydro-1'11- [4,2 '; 4', 4 "] terpyridine-6'-one; 1- (23-hydroxy-propyl) -1'-methyl-5'-naphthalene-2 -Yl-1,2,3,4,5,6-hexahydro-1'11- [4,2 '; 4', 4 "] terpyridin-6'-one; 1- (2-hydroxy-2 -Methyl-propyl) _1'-methyl-5'-fluoren-2-yl-1,2,3,4,5,6_hexahydro-1,11- [4,2 '; 4', 4 "] Terpyridine-6'-one; Isopropyl- [1- (6-naphthalene-2-yl-5-P ratio bite-4-yl-kinethridine-3-ylpyridol-2-ylmethyl] -amine; 6- [5- (Hydroxymethyl) pyrrolidin-3-yl] -1-methyl-3- (2-fluorenyl) -4- (4-pyridyl) -feng'edian-2 -fluorene, 6- [5- (Hydroxymethyl) · 1- (methylethyl) pyrrolidin-3-yl] -1-methyl-3- (2 • naphthyl) _4- (4_pyridyl) azepine- 2- 嗣; 3- (4-chlorophenyl) -6- [2- (hydroxymethyl) pyrrolidinyl] -1-methyl-4- (4-pyridinyl) -peptide-2 -Fluorene, [(111) -fluorenyl-2- (1'-methyl_5'_fluoren-2-yl_6'_oxy-3,4,5,6,1 ', 6'-hexahydro -2H- [4,2 '; 4', 4 "] terpyridine_1-yl) -ethyl] -aminocarboxylic acid tertiary-85481 200406399 butyl ester; 1-{(2R) -amino-3 -Phenyl-propyl} -1'-methyl-5'-naphthalen-2-yl-1,2,3,4,5,6-hexahydro-1,: ^ [4,2 '; 4, , 4, '] terpyridine-6, -one; 1 · {(2R) -isopropylamino-3 -phenyl-propyl} -1' · methyl-5 '-naphthalene-2_yl- 1,2,3,4,5,6-hexahydro-1'11- [4,2 ,; 4 ', 4 ,,] terpyridine-6'-one; [(1S) -fluorenyl-2- (1'-methyl, 5'-naphthalene-2_yl-6'-oxyl-3,4,5,6,1 ', 6'-ττ -2Η- [4,2 '; 4', 4 "] terpyridine-1 -yl) -ethyl] -aminocarboxylic acid third-butyl ester; 1-{(2S) -amino-3- -Propyl} _1'-methyl-5'-naphthalen-2-yl-1,2,3,4,5,6-hexahydro-1,11- [4,2 ,; 4 ', 4 " ] Terpyridine-6, _one; 1-{(2S) -isopropylamino · 3-phenyl-propyl} -1'-methyl-5'_fluoren-2-yl-1,2, 3,4,5,6-hexahydro-1,11- [4,2 ,; 4 ', 4,'] terpyridine-6, -one; {2- [3- (1-methyl-5_ Naphthalene-2 -yl-6-oxy-1,6-dichloro- [4,4,] bi-pyridine-2-yl) -0 pilodian-1-yl] -ethyl} -aminocarboxylic acid Tertiary-butyl hydrazone; 6- [1- (2--Control-propyl) -p-bilodine-3-yl] -1 -methyl_3-naphthalene-2_yl-1Η- [4,4 '] Bipyridyl-2-one; 6- [1- (2-hydroxy-2-methyl-propyl) -pyrrolidin-3-yl] -1-methyl-3-fluoren-2-yl- 1Η- [4,4 '] bipyridyl-2-one; {2- [2- (1-methyl-5-fluoren-2-yl-6-oxy-1,6-dihydro- [4, 4 '] bipyridin-2-yl) -pyrrolidin-1-yl] -ethyl} -aminocarboxylic acid third-butyl ester; 6- [1- (2-amino-ethyl) -π ratio Luodian-2 -yl] _1-methyl-3 -naphthalen-2-yl-1fluorene- [4,4 '] bipyridyl-2-one; 5-chloro-6- [2- (isopropylamine) Methyl-methyl) -Pyrrolidin-1-yl] · 1-methyl-3-fluorene-2 -yl-1fluorene- [4,4 '] bi-pyridyl-2-fluorene, 200406399 6- [2- (isopropyl Amine-methyl) -pyrrolidine-1_ylbu 1-methyl-3_fluoren-2-yl-1 [-4,4 '] bipyridyl · 2-one; and 3- (4- Chlorophenyl) -1-methyl-6- (2-{[((methylethyl) amino] methyl} pyrrolidinyl) -4- (4 ^ biphenyl)) ketone. 6 · A kind of manufacturing according to the scope of patent application! A method of a compound of the invention, which comprises R ^ R2, wherein R1 contains a secondary ring nitrogen, and CI. Γ reaction steps. 7. A method for preparing a medicament containing an effective amount of a compound according to any one of claims 1 to 5. 8. Manufacture of a medicament for the treatment of inflammation, which contains an effective amount of a compound according to any one of claims 1 to 5 of the patent application. 9. The manufacture of a medicament for the treatment of pain, which contains an effective amount of a compound according to any one of claims 1 to 5 of the patent application. ιο · — a kind of treatment for mammalian rheumatoid arthritis, Pagets disease, osteoporosis' multiple myeloma, chromatitis, acute or chronic leukemia produced in the bone marrow, pancreatic beta cell destruction, osteoarthritis, Rheumatoid spondylitis' gout arthritis, inflammatory colitis, adult respiratory depression syndrome (ARDS) 'Psoriasis' Crohn's disease, allergic rhinitis, ulcerative colitis, allergies, contact dermatitis, asthma, muscle degeneration , Cachexia 'Reiter's syndrome, type I diabetes, π diabetes, bone resorption disease' graft-host response, Alzheimer's disease, stroke, myocardial embolism, 85481 200406399 ischemia reperfusion injury , Atherosclerosis, brain injury, multiple sclerosis, cerebral malaria, toxemia, toxic shock, toxic shock syndrome, fever, and muscle pain caused by HIV-1, HIV-2, HIV-3, giant Manufacture of medicines for cytovirus (CMV), influenza, adenovirus, oncovirus, or ribbon cancerous infection, which contain an effective amount according to any of claims 1 to 5 of the scope of patent application Paragraph compound. 85481 200406399 柒. Designated representative map: (* 1) The designated representative map in this case is the brother () map. (2) Brief description of the component representative symbols of this representative map: 捌. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention 85481